Methods for treating cancer, glioblastoma, metastases, and UPS in a subject, and kit.

Description

70 Methods for treating cancer, glioblastoma, metastases, and UPS in a subject, and a kit. Cross-reference to related requests.

[001] This application claims priority over U.S. Provisional Application No. 63 / 447,628, filed February 22, 2023, entitled “COMPOSITIONS AND METHODS FOR TARGETING TUMORASSOCIATED MACROPHAGES,” the contents of which are incorporated herein by reference in their entirety. Field

[002] This disclosure provides a method of treating a disease or disorder comprising administering a composition comprising a compound to a subject, wherein the compound comprises a targeting fraction, a glucan structure and an active component. This disclosure also provides methods of targeting monocytes, macrophages, dendritic cells and other cells that assemble at disease sites, comprising administering a composition comprising a compound to a subject, wherein the compound comprises a targeting fraction, a glucan structure and an active component. Background

[003] The treatment of solid tumors has recently improved with the advent of a wide range of targeted therapies, such as small molecules and biologics. Small molecules have excellent penetrance in solid tumors, but many of them work by inhibiting signal transduction pathways, leading to growth inhibition rather than direct tumor cytotoxicity. If the entire tumor is not eliminated, cancer cells may develop resistance to the small molecule. Biologics, such as antibodies and antibody-drug conjugates (ADCs), can have great potency against certain malignancies and exhibit stability. Petition 870260084360, dated 08 / 20 / 2026, page 10 / 79 / 70 favorable in the blood. However, antibodies have limited penetrance in solid tumors, and tumor cells can develop resistance to ADCs through a variety of cellular modifications (Collins, et al. Acquired Resistance to Antibody-Drug Conjugates. Cancers (Basel) 11, (2019)). Improved methods are needed to target, penetrate, and kill cancer cells in a solid tumor. Modalities that address these needs are provided. Summary

[004] A method of treating a cancer in a subject is provided herein, the method comprising administering to the subject with the cancer, a composition comprising a compound comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan structure, wherein the glucan structure comprises a plurality of structure monomers; iii) an active component, wherein the active component is coupled to the glucan structure; and iv) a targeting linker that links the targeting fraction to the glucan structure, wherein the targeting linker comprises a carbamate group and a chain fraction, and wherein the carbamate group is connected to a structure monomer and the chain fraction connects the carbamate group and the tumor-associated macrophage targeting fraction.

[005] In some embodiments, the plurality of backbone monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic linkage or a beta-1,4 glycosidic linkage. In some embodiments, the plurality of D-glucose monomers is n, where n = 5 to 167. In some of any embodiments, the plurality of D-glucose monomers is n, where n = 50 to 65. In some of any embodiments, the glucan backbone is a linear dextran molecule. In some of any embodiments, the glucan backbone is a cyclodextrin molecule, where n = 6 to 16. Petition 870260084360, dated 08 / 20 / 2026, p. 11 / 79 / 70

[006] In some of any embodiments, the tumor-associated macrophage targeting fraction comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or fragments thereof, or chondroitin sulfate. In some of any embodiments, the targeting fraction is mannose. In some embodiments, the ratio of mannose to backbone monomers is from about 1 to 5 to about 1 to 33. In some of any embodiments, the ratio of mannose to backbone monomers is from about 1 to 6 to about 1 to 19. In some of any embodiments, the degree of mannose substitution in a cyclodextrin ranges from about 0.1 to about 7. In some embodiments, the degree of mannose substitution in a cyclodextrin ranges from about 0.5 to 5.

[007] In some of any embodiments, the targeting ligand is connected to the glucan backbone via the oxygen atom of the carbamate group. In some of any embodiments, the chain fraction of the targeting ligand comprises a C3-C7 alkylene chain. In some of any embodiments, the chain fraction of the targeting ligand comprises a C6-alkylene fraction. In some of any embodiments, the chain fraction of the targeting ligand is a C6-alkylene fraction. In some of any embodiments, the carbon atom of the carbamate group of the targeting ligand is the only sp2 hybridized carbon when said ligand is linked to mannose. In some of any embodiments, the tumor-associated macrophage targeting fraction is a fraction targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL).In some modalities, the tumor-associated macrophage targeting fraction is a CD206 targeting fraction.

[008] In some of any forms, the compound has a Petition 870260084360, dated 20 / 08 / 2026, p. 12 / 79 / 70 molar ratio between the TAM targeting fraction and the active component of about 1:1 to about 1:10. In some of any embodiments, the molar ratio between the TAM targeting fraction and the active component is about 1:1, about 1:2, or about 1:3. In some of any embodiments, the active component is coupled to the glucan backbone via a payload ligand. In some of any embodiments, the active component is a cytotoxic agent.In some embodiments, the cytotoxic agent is selected from the group consisting of an auristatin, a dolastatin, auristatin E, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), dimethylvaline-valine-dolaisoleukin-dolaprotein-phenylalanine-p-phenylenediamine (AFP), auristatin E ester of 5-benzoylvaleric acid (AEVB), auristatin EB (AEB), ansamitocin, ivlertansine / emtansine (DMI), ravtansine / soravtansine (DM4), duocarmycins, calicheamicins, and pyrrolobenzodiazepines. In some embodiments, the cytotoxic agent is MMAE.

[009] In some embodiments, the payload ligand is a non-cleavable ligand. In some embodiments, the payload ligand comprises a carbamate group and a chain fragment, wherein the carbamate group is connected to the backbone monomer and the chain fragment connects the carbamate group and the active component. In some embodiments, the payload ligand is a cleavable ligand. In some embodiments, the cleavable ligand is capable of being cleaved by a protease. In some embodiments, the protease is a lysosomal protease or an endosomal protease. In some embodiments, the cleavable ligand is capable of being cleaved by a pH change. In some embodiments, the payload ligand comprises a Val-Cit fraction.

[0010] In any of the modalities, cancer is a solid tumor selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, glioma, leukemia, lymphoid malignancies, cancer of the cells. Petition 870260084360, dated 08 / 20 / 2026, page 13 / 79 / 70 squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, gallbladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In some forms, the solid tumor is sarcoma or glioblastoma. In some forms, the cancer is a soft tissue sarcoma. In some forms, the cancer is undifferentiated pleomorphic sarcoma (UPS).

[0011] In some of any embodiments, the subject and / or the cancer (a) is resistant to temozolomide (TMZ) and / or doxorubicin and / or (b) comprises a population of cells that are resistant to inhibition by TMZ and / or doxorubicin. In some of any embodiments, the composition is administered to the subject six times daily, five times daily, four times daily, three times daily, twice daily, once daily, on alternate days, three times weekly, twice weekly, at least once weekly, once weekly, once every two weeks, once every three weeks, once monthly, once every two months, or once every three months. In some embodiments, the composition is administered to the subject once every two weeks, once every three weeks, or once monthly.

[0012] In some of the modalities, the method also includes the administration of one or more additional therapeutic agents, adjuvant therapy and / or radiotherapy to the subject. In some modalities, one or more additional active agents are selected from the group consisting of Petition 870260084360, dated 08 / 20 / 2026, page 14 / 79 / 70 chemotherapeutic agents, DNA hypomethylating agents, alkylating agents, topoisomerase inhibitors, therapeutic antibodies that bind specifically to cancer antigens, hematopoietic growth factors, cytokines, antibiotics, cox-2 inhibitors, CDK inhibitors, immunomodulators, antithymocyte globulin, immunosuppressants, and corticosteroids or pharmacological derivatives thereof. In some embodiments, one or more additional active agents are a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is TMZ, doxorubicin, and / or paclitaxel. In some embodiments, the chemotherapeutic agent is administered before, simultaneously with, and / or after the start of administration of the composition to the subject. In some modalities, adjuvant therapy and / or radiotherapy is administered before, simultaneously with, and / or after the start of administration of the compound to the subject.

[0013] In any of the embodiments, the composition is administered to the subject intravenously, intraperitoneally, subcutaneously, intramuscularly, intracranially, or by infusion pump. In some embodiments, the composition is administered intravenously or by pump infusion to the subject.

[0014] A method for treating glioblastoma in a subject is provided herein, the method comprising administering to the subject with glioblastoma a composition comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan structure, wherein the glucan structure comprises a plurality of structure monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan structure; and iv) a targeting linker linking the targeting fraction to the glucan structure, wherein the targeting linker comprises a carbamate group and a chain fraction, and wherein the carbamate group is connected to a structure monomer and the chain fraction connects the carbamate group and the targeting fraction. Petition 870260084360, dated 08 / 20 / 2026, page 15 / 79 / 70 tumor-associated macrophage, in which the subject and / or the glioblastoma (a) are resistant to TMZ and / or (b) comprise a population of cells that are resistant to inhibition by TMZ.

[0015] A method for treating brain metastases in a subject is provided herein, the method comprising administering to the subject with brain metastases a composition comprising: i) a targeting fraction for tumor-associated macrophages (TAM); ii) a glucan framework, wherein the glucan framework comprises a plurality of framework monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan framework;and iv) a targeting ligand that links the targeting moiety to the glucan backbone, wherein the targeting ligand comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the targeting moiety to tumor-associated macrophages, wherein the subject and / or brain metastases (a) are resistant to TMZ and / or (b) comprise a population of cells that are resistant to inhibition by TMZ.

[0016] A method for treating UPS in a subject is provided herein, the method comprising administering to the subject having UPS a composition comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan structure, wherein the glucan structure comprises a plurality of structure monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan structure; and iv) a targeting linker linking the targeting fraction to the glucan structure, wherein the targeting linker comprises a carbamate group and a chain fraction, and wherein the carbamate group is connected to a structure monomer and the chain fraction connects the carbamate group and the targeting fraction. Petition 870260084360, dated 20 / 08 / 2026, p. 16 / 79 / 70 tumor-associated macrophage, in which the subject and / or UPS (a) is resistant to doxorubicin and / or (b) comprises a population of cells that are resistant to doxorubicin.

[0017] In any given embodiment, the plurality of backbone monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic linkage or a beta-1,4 glycosidic linkage. In any given embodiment, the plurality of D-glucose monomers is n, where n = 5 to 167. In any given embodiment, the plurality of D-glucose monomers is n, where n = 50 to 65. In any given embodiment, the glucan backbone is a linear dextran molecule. In any given embodiment, the glucan backbone is a cyclodextrin molecule, where n = 6 to 16.

[0018] In some of any embodiments, the tumor-associated macrophage targeting fraction comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or fragments thereof, or chondroitin sulfate. In some of any embodiments, the targeting fraction is mannose. In some embodiments, the ratio of mannose to backbone monomers is from about 1 to 5 to about 1 to 33. In some of any embodiments, the ratio of mannose to backbone monomers is from about 1 to 6 to about 1 to 33. In some of any embodiments, the degree of mannose substitution in a cyclodextrin ranges from about 0.1 to about 7. In some of any embodiments, the degree of mannose substitution in a cyclodextrin ranges from about 0.5 to 5.In any embodiment, the targeting ligand is connected to the glucan backbone via the oxygen atom of the carbamate group. In any embodiment, the chain fraction of the targeting ligand comprises a C3-C7 alkylene chain. Petition 870260084360, dated 20 / 08 / 2026, p. 17 / 79 / 70 in some of any embodiments, the chain fraction of the targeting ligand comprises a C6-alkylene fraction. In some of any embodiments, the chain fraction of the targeting ligand is a C6-alkylene fraction.

[0019] In some embodiments, the carbon atom of the carbamate group of the targeting ligand is the only sp2 hybridized carbon when said ligand is linked to mannose. In some embodiments, the tumor-associated macrophage targeting fraction is a fraction targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL). In some embodiments, the tumor-associated macrophage targeting fraction is a CD206 targeting fraction. In some embodiments, the compound has a molar ratio between the TAM targeting fraction and the active component of about 1:1 to about 1:10. In some of the modalities, the molar ratio between the TAM targeting fraction and the active component is approximately 1:1, approximately 1:2, or approximately 1:3.

[0020] In some embodiments, the active component is coupled to the glucan backbone via a payload linker. In some embodiments, the payload linker is a non-cleavable linker. In some embodiments, the payload linker comprises a carbamate group and a chain fragment, wherein the carbamate group is connected to the backbone monomer and the chain fragment connects the carbamate group and the active component. In some embodiments, the payload linker is a cleavable linker. In some embodiments, the cleavable linker is capable of being cleaved by a protease. In some embodiments, the protease is a lysosomal protease or an endosomal protease. In some embodiments, the cleavable linker is capable of being cleaved by a pH change. In some embodiments, the payload linker comprises a Val-Cit fraction. Petition 870260084360, dated 08 / 20 / 2026, page 18 / 79 / 70

[0021] In some of the modalities, the method also comprises administering radiation therapy to the subject. In some of the modalities, the method also comprises administering TMZ and / or doxorubicin to the subject. In some of the modalities, the method attenuates tumor growth in the subject. In some of the modalities, the subject is immunocompetent or immunocompromised. In some modalities, the method comprises: i) the tumor-associated macrophage (TAM) targeting fraction is a CD206 targeting fraction; and ii) the active component is coupled to the glucan backbone via a payload ligand, where the active component is MMAE and the payload ligand is a Val-Cit ligand.In any embodiment, the method comprises: i) the tumor-associated macrophage (TAM) targeting fraction is a CD206 targeting fraction; and ii) the active component is coupled to the glucan backbone via a payload ligand, where the active component is MMAE and the payload ligand is a Val-Cit ligand. In any embodiment, the method comprises administering Compound A to the subject.

[0022] A kit comprising a composition comprising a compound is provided herein, wherein the compound comprises: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan structure, wherein the glucan structure comprises a plurality of structure monomers; iii) an active component, wherein the active component is coupled to the glucan structure; and iv) a targeting linker linking the targeting fraction to the glucan structure, wherein the targeting linker comprises a carbamate group and a chain fraction, and wherein the carbamate group is connected to a structure monomer and the chain fraction connects the carbamate group and the tumor-associated macrophage targeting fraction; and instructions for administration to a subject. Petition 870260084360, dated 08 / 20 / 2026, page 19 / 79 / 70 for cancer treatment. Brief Description of the Drawings

[0023] FIG. 1 is a graphical representation of a candidate compound, in which a tumor-associated macrophage (TAM) target fraction molecule is labeled with MMAE.

[0024] FIGS. 2A, B represent the therapeutic effect of Target 5 on tumor volume (FIG. 2A) and body weight (FIG. 2B) in a subcutaneous HT1080 fibrosarcoma model.

[0025] FIG. 3 represents the therapeutic effect of Target 5 on tumor size (measured by bioluminescence) in an intracranial challenge with HT1080 cells in an STS brain metastasis model.

[0026] FIGS. 4A-D represent the efficacy of Target 5 in the doxorubicin-resistant UPS PDX model. FIGS. 4A and 4B show the effect of Target 5 on tumor volume. FIGS. 4C shows the effect of Target 5 on tumor volume compared to doxorubicin. Representative mouse tumors in each treatment group were excised (FIG. 4D).

[0027] FIGS. 5A, B represent the effectiveness of Target 5 on tumor volume (FIG. 5A) and body weight (FIG. 5B) in a subcutaneous glioma model (U87MG cell line).

[0028] FIGS. 6A-6C represent the efficacy of Target 5 on tumor volume (FIG. 6A and FIG. 6C) and body weight (FIG. 6B) in immunocompetent mice subcutaneously implanted with GL261 tumor cells (moderately resistant to temozolomide).

[0029] FIG. 7 represents the plasma concentration of free MMAE in mice after administration of Target 5.

[0030] FIGS. 8A, 8B show that Target 5 exhibits anticancer efficacy in a PDX model of an undifferentiated pleomorphic sarcoma, naive to therapy. Mean tumor volumes (FIG. 8A) and body weight (FIG. 8B) are shown. Petition 870260084360, dated 08 / 20 / 2026, page 20 / 79 / 70

[0031] FIGS. 9A (tumor volume) and 9B (histology of excised tumor) show that Target 5 exhibits anticancer efficacy, while Compound B (Target 5 without MMAE) lacks anticancer activity.

[0032] FIG. 10 represents the anticancer efficacy of Target 5 in a PDX model of myxofibrosarcoma compared to doxorubicin. Detailed Description

[0033] Methods of treating a disease or disorder are provided herein, wherein the method comprises administering a composition comprising a compound to a subject, wherein the compound comprises a targeting fraction, a glucan backbone, and an active component. In some embodiments, the targeting fraction is a tumor-associated macrophage targeting fraction. In some embodiments, the method comprises administering the compound to target monocytes, macrophages, and other cells (such as dendritic cells), particularly those cells that are clustered at a site of disease. In some embodiments, the targeting fraction (e.g., a tumor-associated macrophage targeting fraction) is coupled to a glucan backbone.In certain embodiments, the method comprises administering a composition comprising a compound, wherein the compound comprises a glucan structure, a targeting fraction, a targeting fraction ligand, a payload and, optionally, a payload ligand.

[0034] CD206+ cells, particularly macrophages, have been targeted by several molecules in the hope of delivering diagnostic and therapeutic agents to the sites where these cells congregate. An example of such molecules is found in US patent 2017 / 0209584, entitled “Compositions to target macrophages and other high-CD206 expressing cells and methods for treatment and diagnosis”. While the molecules disclosed in this reference and others may target CD206+ cells Petition 870260084360, dated 08 / 20 / 2026, page 21 / 79 / 70 interest, the molecules suffer from a series of deficiencies.

[0035] Soft tissue sarcomas (STS) are rare but deadly cancers of children and adults. The American Cancer Society estimates about 13,000 new cases of STS each year in the United States, with about 5,130 expected deaths and a 5-year overall survival rate for metastatic disease of only 16%. Conventional treatments, including surgery, chemotherapy, and radiation therapy, have had limited success in treating STS. For example, undifferentiated pleomorphic sarcoma (UPS), a highly aggressive adult sarcoma, has a median overall survival rate for metastatic UPS of only 15.5 months. An aggressive sarcoma associated with adolescence, Ewing sarcoma / primitive neuroectodermal tumor (PNET), has a five-year survival rate of only 15% for metastatic cases.

[0036] Doxorubicin (DOX) is one of the most active drugs available for the treatment of sarcoma and is generally the first-line treatment for undifferentiated / unclassified STS, although doxorubicin cardiotoxicity can be dose-limiting. Response rates to treatment with doxorubicin alone decrease significantly after exposure to the drug, indicating that increasing resistance to doxorubicin may lead to treatment failure (Das, B. et al. Commun Biol 4, 1312 (2021)).

[0037] Glioblastoma multiforme (GBM) is a devastating and almost always fatal cancer. Treatment involves surgery, radiation with concurrent temozolomide (TMZ), followed by 6 to 12 months of maintenance with TMZ. Despite maximum treatment, 50% of people diagnosed with GBM die within 12 to 15 months of diagnosis. Treatment is arduous and often comes with the added burden of increasing neurological deficits. These symptoms can have a huge impact on the patient and their family. GBM has not had a new drug therapy approved that prolongs survival since TMZ was approved in 2017. Petition 870260084360, dated 08 / 20 / 2026, p. 22 / 79 / 70 2005. Even with the addition of Optune (Novocure, St. Helier, Jersey), an alternating electric field electrode device, the 5-year survival rate of GBM is only 13% (Stupp et al., JAMA. 2017; 318(23):2306-2316).

[0038] Although TMZ is the first-line chemotherapy drug for the treatment of GBM, resistance and tumor recurrence are almost inevitable. Due to widespread exposure to TMZ and the highly heterogeneous and mutation-prone nature of GBM, it is quite common for GBM tumors to develop resistance to TMZ. Currently, more than 50% of GBM patients treated with TMZ do not respond to therapy (Singh et al. Cancer Drug Resist. 2021; 4(1): 17-43). To treat drug-resistant cancers (e.g., soft tissue sarcomas and glioblastoma), there is a great need for novel treatments with limited toxicities.

[0039] New tumor-independent approaches are needed to overcome the limitations of the current state of the art and further improve treatment outcomes. As an example, STS encompasses more than 50 different histological and molecular subtypes, each exhibiting variable clinical behavior (Katz et al., “More than 50 soft tissue sarcoma subtypes: paving the way for histology-based treatments” Am Soc Clin Oncol Educ Book, 2018, 38, 925-938). Due in part to this variability, current treatment options have shown limited efficacy, and there are no single or combination treatments that can consistently and effectively treat all STS subtypes.

[0040] Tumors are frequently characterized by a high ratio of tumor-associated macrophages (TAMs); often representing 30-50% or more of the total cells in a tumor (Vinogradov et al., Nanomedicine (Lond). 2014 Apr; 9(5): 695-707). Targeting TAMs as recipient cells for the delivery of tumor-destroying payloads has the advantage of allowing local administration of anticancer therapy without negatively affecting TAMs. This approach also Petition 870260084360, dated 08 / 20 / 2026, page 23 / 79 / 70, circumvents the difficulties of targeting heterogeneous cancer cells, as well as overcoming most types of resistance in evolved cancer cells. Treatment methods are provided here that circumvent concerns about tumor heterogeneity and evolved resistance to drugs associated with current therapies (e.g., doxorubicin, temozolomide). Treatment methods are provided here that ignore specific properties of each type of cancer.

[0041] All publications, including patent documents, scientific articles and databases, mentioned in this application are incorporated by reference in their entirety for all purposes, to the same extent as if each individual publication were incorporated individually by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications incorporated herein by reference, the definition set forth herein shall prevail over the definition which is incorporated herein by reference.

[0042] The section headings used in this document are for organizational purposes only and shall not be construed as limiting the subject matter described. I. Compounds

[0043] Methods for treating a disease or disorder (e.g., cancer) in a subject are provided herein, wherein the methods comprise administering a composition comprising a compound. In some embodiments, the compound comprises a glucan structure, a targeting fraction, a targeting fraction linker, a payload, and optionally a payload linker. In some embodiments, the arrangement of these components provides a compound that targets tumor-associated macrophages (TAMs). In some embodiments, the methods disclosed herein utilize TAMs as cells Petition 870260084360, dated 08 / 20 / 2026, page 24 / 79 / 70 receptors to collect, process, and deliver payloads to the tumor environment. For example, sarcomas are characterized by abundant tumor-associated macrophages (TAMs) (Fujiwara et al., “Role of tumor-associated macrophages in sarcomas” Cancers (Basel), 2021, 13(5):1086). Anti-CD206 immunohistochemistry in a human sarcoma tissue matrix, including 59 specimens spanning 19 sarcoma subtypes, demonstrated high and relatively uniform expression of this TAM receptor in essentially all specimens.

[0044] In some embodiments, the method involves the internalization of the administered compound by cells (e.g., CD206+ cells) present in tumor-associated macrophages. The ability to be internalized by cells present in tumor-associated macrophages allows the administered compounds and compositions to deliver payloads to disease sites where such cells congregate, such as in solid tumor cancers and granulomatous diseases.

[0045] In some embodiments, the methods disclosed herein comprise the administration of a composition comprising a compound in which the compound is larger than typical small molecules but smaller than antibody-drug conjugates, allowing excellent penetration into target sites and minimal leakage into normal tissues, thus limiting potential toxicities. Furthermore, while rapidly dividing, mutating, and heterogeneous cancer cells often develop resistance to traditional therapies, terminally differentiated macrophages do not experience selective pressures to develop resistance to the treatment methods disclosed herein. A. Glucan Backbone

[0046] In certain embodiments, the methods described herein comprise the administration of a compound comprising a glucan structure, which is a linear oligosaccharide or polysaccharide, Petition 870260084360, dated 20 / 08 / 2026, page 25 / 79 / 70 branched or circular comprising a plurality of glucose monomers linked predominantly by C-1 ^ C-6 glycosidic linkages. In certain embodiments, other glycosidic linkages, such as α-1,3 or α-1,4 linkages, may also be present. In some embodiments, the plurality of glucose monomers is linked by α-1,6 and α-1,3 glycosidic linkages. In some embodiments, the plurality of glucose monomers is linked by a mixture of α-1,6 and α-1,4 glycosidic linkages. A glucan backbone may also be defined as a glucose polymer in which the position of the glycosidic linkages is varied.

[0047] In some embodiments, a glucan backbone may also be defined as a glucose polymer in which the position of the glycosidic linkages is varied. In some embodiments, a glucan structure may comprise the alpha or beta isomer of glucose. Glucan backbones include, but are not limited to, dextran, a linear or branched compound, and cyclodextrin, a circular glucan.

[0048] The glucan backbone can vary in mass and molecular weight, as determined in part by the number of glucose monomers. In some embodiments, a glucan backbone can vary in molecular weight from 1 to 30 kilodaltons (kDa). Preferred embodiments include glucan backbones of approximately 1 kDa, 3 kDa, 6 kDa, 10 kDa, 20 kDa, or 30 kDa. In some embodiments, the glucan backbone can vary in molecular mass from 1,000 to 30,000 grams per mole (g / mol). In some embodiments, the glucan backbone can contain glucose monomers ranging from 5 to 167 in number. The glucan backbone can be linear, branched, circular, or combinations thereof. For example, dextran is an example of a linear or branched glucan backbone. Cyclodextrin is another example of a glucan backbone. The backbones described here may be substituted or unsubstituted. For example, a substituted cyclodextrin is a Petition 870260084360, dated 08 / 20 / 2026, page 26 / 79 / 70 derived from cyclodextrin that is hydrophobic, hydrophilic, ionized, non-ionized or any other variation thereof.

[0049] In some embodiments, the glucan backbone comprises a plurality of backbone monomers, wherein the plurality of backbone monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic linkage or a beta-1,4 glycosidic linkage. In a specific embodiment, the plurality of backbone monomers comprises a plurality of D-glucose monomers in a beta-1,4 glycosidic linkage. In some embodiments, the plurality of D-glucose monomers is n, wherein n=16 to 111. In some embodiments, n=50 to 65. In some embodiments, the plurality of D-glucose monomers is n, wherein n=5 to 167. In some embodiments, the glucan backbone is a linear dextran molecule. In some embodiments, the glucan backbone is a cyclodextrin molecule comprising 6 to 16 D-glucose monomers. B. Directional fraction

[0050] In certain embodiments, the method described herein comprises administering a compound comprising a targeting fraction coupled to a glucan backbone. In some embodiments, the targeting fraction is a tumor-associated macrophage targeting fraction. In some embodiments, the targeting fraction binds to a receptor, including but not limited to CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL), which are present in or near a tumor, allowing for targeted delivery of payloads to the tumor. In some embodiments, the targeting fraction is a CD205 targeting fraction. In some embodiments, the targeting fraction is a CD206 targeting fraction. In some embodiments, the targeting fraction is a targeting fraction of Petition 870260084360, dated 08 / 20 / 2026, p. 27 / 79 / 70 In some embodiments, the direction fraction is a direction fraction of CD209. In some embodiments, the direction fraction is a direction fraction of CD280. In some embodiments, the direction fraction is a direction fraction of CD301. In some embodiments, the direction fraction is a CD206 ligand.

[0051] In some embodiments, the target receptor is a tumor-associated macrophage. In some embodiments, the target receptor is a cancer or tumor cell. A targeting fraction may be a molecule, a compound, a structure, or any combination thereof that targets one or more pattern recognition receptors on tumor-associated macrophages or on a cancer or tumor cell. The targeting fraction may target a pattern recognition receptor that may also be characterized as a C-type lectin receptor. In one specific embodiment, the targeting fraction targets CD206, a mannose receptor.

[0052] In some embodiments, the targeting fraction comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or fragments thereof, or chondroitin sulfate. In some embodiments, the targeting fraction comprises a mannose, including D and L isomers thereof. In some embodiments, the targeting fraction comprises a furanose. In some embodiments, the targeting fraction comprises a pyranose. In some embodiments, the targeting fraction is D-mannose. It is understood that the targeting fraction of the tumor-associated macrophage may be referred to as the targeting fraction.

[0053] In some embodiments, the targeting fractions are attached to between about 10% and about 50% of the glucose residues of Petition 870260084360, dated 20 / 08 / 2026, p. 28 / 79 / 70 glucan backbone, or between about 20% and about 45% of glucose residues, or between about 25% and about 40% of glucose residues. C. Ratio of ligand targeting to backbone

[0054] The density of a targeting fraction relative to backbone subunits is presented using a targeting fraction to backbone subunit ratio for linear, branched, or circular polysaccharide backbones. For example, the degree of substitution (ds) is used to communicate the density of targeting fractions in a glucan backbone. The ratio of a targeting fraction to a glucan backbone refers to the number of targeting fractions that substitute one or more backbone subunits. For example, a ratio of 1:7 or 1 to 7 means that there is one targeting fraction for every seven glucose subunits in a glucan backbone. The ds describes the average number of substituents or substituted positions per base unit. For example, a ds of 0.9 means that a backbone subunit is substituted by an average of 0.9 targeting fractions.In some embodiments, the ratio between the targeting fraction and the backbone subunit is from about 1:5 to about 1:25. In some embodiments, the ratio between the targeting fraction and the backbone subunit is from at least 1:50 (e.g., at least 1:33, at least 1:35, at least 1:40, or at least 1:45) to about 1:5. In some embodiments, the ratio between the targeting fraction and the backbone subunit is from about 1:6 to about 1:19. In some embodiments, the ratio between the targeting fraction and the backbone subunit is or is about 1:1. In some embodiments, the ratio between the targeting fraction and the backbone subunit is or is about 2:1. In some embodiments, the ratio between the targeting fraction and the backbone subunit is or is about 3:1. In some disciplines, the ds is around 0.1 to around 7. In some. Petition 870260084360, dated 08 / 20 / 2026, p. 29 / 79 / 70 modalities, the ds is approximately 0.5 to 5. In some modalities, in conjunction with the modalities above or below, the targeting fraction comprises a mannose. D. Targeting Binder

[0055] In certain embodiments, the method described herein comprises administering a compound comprising a targeting moiety coupled to the glucan backbone by a targeting ligand. In one embodiment, the targeting ligand is either a cleavable or a non-cleavable ligand. In some embodiments, a cleavable ligand is capable of being cleaved by an enzyme (e.g., a protease), a temperature change, a pH change, a chemical stimulus, or any combination thereof. In some embodiments, the cleavable ligand may comprise a protease cleavage site. In some embodiments, the cleavable ligand is capable of cleavage by a lysosomal protease or an endosomal protease.

[0056] In some embodiments, the targeting ligand may comprise a carbamate group. In some embodiments, the targeting ligand comprises a carbamate group and a chain fraction, wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the targeting component. As provided herein, a carbamate functional group assumes the simple and common meaning derived from the field of organic chemistry. In some embodiments, the chain fraction of the targeting ligand comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an optionally substituted O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain fraction of Petition 870260084360, dated 20 / 08 / 2026, p. 30 / 79 / 70 The chain comprises a C1-C12 alkylene chain. In some embodiments, the chain fraction comprises a C3-C7 alkylene chain. In some embodiments, the chain fraction comprises a C6 alkylene chain. In some embodiments, the chain fraction is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH2, SH, C1-C12 alkyl, C1-C12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1-C12 alkyl)2, N(C1-C12 haloalkyl)2, S(C1-C12 alkyl), S(C1-C12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C1-C12 haloalkyl), C(O)NH(C1-C12 alkyl), C(O)NH(C1-C12 haloalkyl), C(O)N(C1-C12 alkyl)2, C(O)N(C1-C12 haloalkyl)2, C(O)S(C1-C12 alkyl), and C(O)S(C1-C12 haloalkyl). In some embodiments, the alkylene chain is unsubstituted.

[0057] In some embodiments, one or more targeting moieties are linked to the glucan backbone by means of a linker. The linker may be linked to about 1 to about 50% of the backbone moieties. In some embodiments, the targeting linker comprises a C1-12 alkylene chain and a carbamate group, wherein the carbamate group is connected to the backbone monomer and the C1-12 alkylene chain connects the carbamate group and the targeting moiety. E. Active Component

[0058] In certain embodiments, the method described herein comprises the administration of a compound comprising an active component. In some embodiments, an active component is a molecule or compound that can be used for diagnostic, therapeutic, or a combination thereof purposes. An active component is also called a payload. In some embodiments, an active component may be or comprise a cytotoxic agent, an imaging agent, or a combination thereof. In some embodiments, a payload may facilitate the targeted delivery of Petition 870260084360, dated 08 / 20 / 2026, page 31 / 79 / 70 compounds described herein to macrophages or tumor-associated cancer cells. In some embodiments, the payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the payload is a hydrophilic payload.

[0059] In some embodiments, the active component is a therapeutic agent. The therapeutic agent may be any compound known to be useful for the treatment of a macrophage-mediated disease. Therapeutic agents include, but are not limited to, chemotherapeutic agents such as doxorubicin; alkylating agents such as temozolomide; anti-infective agents such as antibiotics (e.g., tetracycline, streptomycin, rifampicin, and isoniazid), antivirals, antifungals, and antiparasitics; immunoadjuvants; steroids; nucleotides such as DNA, RNA, RNAi, siRNA, CpG, or Poly(I:C); peptides; proteins; antibody-drug conjugates (e.g., trastuzumab deruxtecan); or metals such as silver, gallium, or gadolinium.

[0060] In some embodiments, the therapeutic agent is selected from a group that includes, but is not limited to, cytostatic agents, alkylating agents, antimetabolites, antiproliferative agents, tubulin-binding agents, hormones and hormone antagonists, anthracycline drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, pteridine drugs, diinenes, podophyllotoxins, toxic enzymes, and radiosensitizing drugs.

[0061] In some embodiments, the therapeutic agent is selected from the group consisting of lomustine, epirubicin, topotecan, irinotecan, pemetrexed, docetaxel, oxaliplatin, altretamine, valrubicin, sarcine, temozolomide, mechlorethamine, triethylenephosphoramide, cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, triaziquone, nitrosourea compounds, adriamycin, carminomycin, daunorubicin (daunomycin), Petition 870260084360, dated 08 / 20 / 2026, page. 32 / 79 / 70 doxorubicin, isoniazid, rifampicin, indomethacin, gallium(III), 68-gallium(III), aminopterin, methotrexate, metopterin, mithramycin, streptonigrin, dichlormethotrexate, mitomycin C, actinomycin-D, porfiromycin, 5-fluorouracil, floxuridine, ftorafur, 6-mercaptopurine, cytarabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, taxol, taxane, cytochalasin B, gramicidin D, ethidium bromide, emetine, tenoposide, colchicine, dihydroxyanthracinedione, mitoxantrone, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin A subunit, abrin, diphtheria toxin, botulinum toxin, cyaninosins, saxitoxin, shigatoxin, tetanus, tetrodotoxin, trichothecene, verrucologen, corticosteroids, progestins, estrogens, antiestrogens, androgens, aromatase inhibitors, calicheamicin, esperamycins, deruxtecan, and dynemycins.

[0062] In any embodiment, the active component is a cytotoxic agent or comprises a cytotoxic agent. In some embodiments, the cytotoxic agent is a chemotherapeutic agent, an anti-tubulin agent, a DNA-modifying agent, or a small interfering ribonucleic acid. In some embodiments, the cytotoxic agent is selected from the group consisting of auristatin, dolastatin, auristatin E, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), dimethylvaline-valine-dolaisoleukin-dolaproin-phenylalanine-p-phenylenediamine (AFP), auristatin E ester of 5-benzoylvaleric acid (AEVB), auristatin EB (AEB), ansamitocin, ivlertansine / emtansine (DMI), ravtansine / soravtansine (DM4), duocarmycins, calicheamicins, and pyrrolobenzodiazepines. In one specific embodiment, the active component is MMAE. F. Payload Connector

[0063] In certain embodiments, the active component or payload is coupled directly to the glucan backbone. In some embodiments, Petition 870260084360, dated 20 / 08 / 2026, p. 33 / 79 / 70 the active component is connected to a glucan backbone via a linker. The linker may be cleavable or non-cleavable. In some embodiments, one or more therapeutic agents are linked via a biodegradable linker. In some embodiments, the biodegradable linker is acid-sensitive, such as a hydrazone linker. The use of an acid-sensitive linker allows the drug to be transported into the cell and allows for substantial drug release within the cell. In some embodiments, the payload linker is a Val-Cit linker.

[0064] In some embodiments, the payload ligand may comprise a carbamate group. In some embodiments, the payload ligand comprises a carbamate group and a chain fraction, wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the active component. In this document, a carbamate functional group assumes the simple and common meaning derived from the field of organic chemistry. In some embodiments, the chain fraction of the payload ligand comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an optionally substituted O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain moiety comprises a C1-C12 alkylene chain.In some embodiments, the chain fraction comprises a C3C7 alkylene chain. In some embodiments, the chain fraction comprises a C6 alkylene chain. In some embodiments, the chain fraction is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH2, SH, C1-C12 alkyl, C1-C12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1-C12). Petition 870260084360, of 08 / 20 / 2026, p. 34 / 79 / 70 alkyl)2, N(C1-C12 haloalkylK, S(C1-C12 alkyl), S(C1-C12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C1-C12 haloalkyl), C(O)NH(C1-C12 alkyl), C(O)NH(C1-C12 haloalkyl), C(O)N(C1-C12 alkyl)2, C(O)N(C1-C12 haloalkyl)2, C(O)S(C1-C12 alkyl), and C(O)S(C1-C12 haloalkyl).

[0065] In some embodiments, the molar ratio between the directing fraction (e.g., mannose) and the payload is from about 1:10 to about 10:1. In some embodiments, the molar ratio between the directing fraction and the payload is at least about 1:10 (e.g., about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, and 4:1). In some embodiments, the molar ratio between the directing fraction and the payload is about 1:1. In some embodiments, the molar ratio between the directing fraction and the payload is about 1:2. In some embodiments, the molar ratio between the directing fraction and the payload is about 1:3. In some applications, the molar ratio between the steering fraction and the payload is approximately 1:4.

[0066] In some embodiments, the payload linker comprises a -C(O)-C1-12 alkylene chain and a carbamate group, wherein the carbamate group is connected to the backbone monomer and the -C(O)C1-12 alkylene chain connects the carbamate group and the payload. G. Payloads and secondary binders

[0067] In addition to targeting, diagnostic, and therapeutic payloads, the compounds used in the methods disclosed herein may include secondary agents that can be coupled to the glucan structure to add additional functional capabilities. Typically, the secondary payload is coupled to the ligand in a manner similar to that used to couple the targeting moiety to the targeting ligand. In some embodiments, a secondary payload may facilitate targeted delivery of the compositions described herein to Petition 870260084360, dated 08 / 20 / 2026, p. 35 / 79 / 70 macrophages or cancer cells. In some embodiments, the secondary payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the secondary payload is a hydrophilic payload.

[0068] In some embodiments, a secondary payload may be a radiosensitizer. See, for example, Zhang et al., “Application of Radiosensitizers in Cancer Radiotherapy” Int J Nanomedicine, 2021, 16:1083-1102. In some embodiments, the radiosensitizer is a small molecule radiosensitizer including, but not limited to, monomethyl auristatin E (MMAE), mitomycin C, misonidazole, curcumin, or paclitaxel. In some embodiments, a secondary payload may be an antituberculosis drug (e.g., rifampicin or isoniazid).

[0069] A secondary payload may include, for example, additional agents for imaging, therapy, or other purposes. Specifically, in one modality, combinations of therapeutic and imaging agents may be linked to the glucan backbone to combine diagnostic and therapeutic functionalities. In another modality, various amino acids, such as cysteine ​​or lysine, may be coupled to the ligand to crosslink the molecule to a target.

[0070] A secondary charge linker is a cleavable or non-cleavable linker that connects a glucan backbone to a secondary charge moiety. A cleavable linker is capable of being cleaved by an enzyme (e.g., a protease), a change in temperature, a change in pH, a chemical stimulus, or any combination thereof. The cleavable linker may comprise a protease cleavage site. In some embodiments, the cleavable linker is capable of cleavage by a lysosomal protease or an endosomal protease.

[0071] The secondary payload linker may comprise a carbamate group. In some embodiments, the secondary payload linker Petition 870260084360, dated 20 / 08 / 2026, p. 36 / 79 / 70 comprises a carbamate group and a chain fraction, wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the secondary agent. In this document, a carbamate functional group assumes the simple and common meaning derived from the field of organic chemistry. In some embodiments, the chain fraction of the secondary payload ligand comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an optionally substituted O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain moiety comprises a C1-C12 alkylene chain.In some embodiments, the chain fraction comprises a C3C7 alkylene chain. In some embodiments, the chain fraction comprises a C6 alkylene chain. In some embodiments, the chain fraction is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH2, SH, C1-C12 alkyl, C1-C12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1-C12 alkyl)2, N(C1-C12 haloalkyl)2, S(C1-C12 alkyl), S(C1-C12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C1-C12 haloalkyl), C(O)NH(C1-C12 alkyl), C(O)NH(C1-C12 haloalkyl), C(O)N(C1-C12 alkyl)2, C(O)N(C1-C12 haloalkyl)2, C(O)S(C1-C12 alkyl), and C(O)S(C1-C12 haloalkyl). In some embodiments, the alkylene chain is unsubstituted.

[0072] In some embodiments, one or more payload fractions are linked to the glucan backbone by means of a linker. The linker may be linked to about 1 to about 50% of the backbone fractions. II. EXEMPLARY COMPOUNDS

[0073] In some forms, the composition described here Petition 870260084360, dated 08 / 20 / 2026, p. 37 / 79 29 / 70 comprises Compound A or a pharmaceutically acceptable salt thereof: Compound A.

[0074] In some embodiments, monomers of the types labeled a, c, or d in Compound A may be in a block copolymer arrangement or may be randomly arranged within the polymer or any combination thereof, unless otherwise indicated. In some embodiments, a, c, and d of Compound A may each independently refer to an integer from 0, at least 1, from about 1 to about 165, from about 16 to about 111, from about 50 to about 65, from about 5 to about 167, or from about 6 to about 16. In some embodiments, the glucan backbone of Compound A is linear, branched, circular, or combinations thereof. In some embodiments, a terminal group of the glucan backbone of Compound A may be a monomer hydroxyl end group. In some embodiments, a glucan backbone end group of Compound A may be any end group recognizable by one skilled in the art.

[0075] In some embodiments, the glucan backbone of Compound A is linear, branched, circular, or combinations thereof; a, ced are each independently chosen from the group consisting of: a number Petition 870260084360, dated 20 / 08 / 2026, p. 38 / 79 / 70 integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65 and an integer from about 6 to about 16; and the glucan end group is a hydroxyl end group of the monomer. In some embodiments, the glucan backbone of Compound A is circular, and a, ced are each independently elected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16.In some embodiments, the glucan backbone of Compound A is linear; a, ced are each independently chosen from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the glucan backbone terminal group is a monomer hydroxyl end group.In some embodiments, the glucan backbone of Compound A is branched; a, ced are each independently chosen from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the glucan backbone terminal group is a monomer hydroxyl end group.

[0076] In some embodiments, in combination with the embodiments above or below, the glucan backbone of Compound A is approximately 6 kDa, where the glucan backbone is a dextran. In Petition 870260084360, dated 20 / 08 / 2026, p. 39 / 79 / 70 In some embodiments, in combination with the embodiments above or below, the α, β, δ, δ groups of Compound A are interspersed. In some embodiments, in combination with the embodiments above or below, the terminal groups of the glucan backbone are a natural glucose end group, such as a hydroxyl end group. In some embodiments, in combination with the embodiments above or below, the ratio of the targeting fraction to the backbone monomers of Compound A is about 1:30 to 1:40 (e.g., 1:33). In some embodiments, in combination with the embodiments above or below, the ratio of MMAE to mannose of Compound A is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).

[0077] In some embodiments, Compound A is provided herein, in which the glucan backbone is a dextran; the molecular weight of the glucan backbone is about 6 kDa; the α, δc groups are interspersed; the terminal groups of the glucan backbone are a natural glucose terminal group, such as a hydroxyl terminal group; the ratio of the targeting fraction to the backbone monomers is about 1:30 to 1:40 (e.g., 1:33); and the ratio of MMAE to mannose is about 1:1 to 1:3 (e.g., 1:1).

[0078] In some embodiments, Compound A is provided herein, in which the glucan backbone is a dextran; the molecular weight of the glucan backbone is about 6 kDa; the α, δc groups are interspersed; the terminal groups of the glucan backbone are a natural glucose terminal group, such as a hydroxyl terminal group; the ratio of the targeting fraction to backbone monomers is about 1:33 to 1:40 (e.g., 1:37); and the ratio of MMAE to mannose is about 1:3 to 1:5 (e.g., 1:4). III. Pharmaceutical Compositions

[0079] Compositions comprising the are also provided Petition 870260084360, dated 08 / 20 / 2026, page 40 / 79 / 70 compound, including pharmaceutical compositions and formulations. In some embodiments, the method described herein comprises administering the composition for the treatment of a disease. In some embodiments, the disease is cancer. Pharmaceutical formulations comprising the compound and additional agents for treatment or combination therapy are provided. The pharmaceutical compositions and formulations generally include one or more optional pharmaceutically acceptable carriers or excipients. According to some embodiments, the pharmaceutical composition includes at least one additional therapeutic agent.

[0080] The term “pharmaceutical formulation” refers to a preparation whose form allows the biological activity of an active ingredient contained therein to be effective, and which does not contain additional components that are unacceptably toxic to a subject to whom the formulation will be administered. A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than the active ingredient, that is non-toxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0081] In some respects, the choice of carrier is determined in part by the method of administration. Therefore, there is a variety of suitable formulations. For example, the pharmaceutical composition may contain preservatives. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some respects, a mixture of two or more preservatives is used. The preservative or mixtures thereof are typically present in an amount of about 0.001% to about 2% by weight of the total composition. Carriers are described, for example, by Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally non-toxic to receptors at the dosages and Petition 870260084360, dated 20 / 08 / 2026, page 41 / 79 / 70 concentrations employed include, but are not limited to: buffers, such as phosphate, citrate and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (less than about 10 residues); proteins, such as albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol;Salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as polyethylene glycol (PEG).

[0082] Buffering agents are in some respects included in the compositions. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some respects, a mixture of two or more buffering agents is used. The buffering agent or mixtures thereof are normally present in an amount of about 0.001% to about 4% by weight of the total composition. The methods for preparing such compositions are well known in the pharmaceutical industry. Exemplary methods are described in more detail, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st edition. (May 1, 2005).

[0083] The formulation or composition may also contain more than one active ingredient useful for the particular indication, disease, or condition being treated with the compound or composition. Such active ingredients are duly present in combination in amounts that are effective for Petition 870260084360, dated 08 / 20 / 2026, page 42 / 79 / 70 the intended purpose. Thus, in some embodiments, the pharmaceutical composition also includes other pharmaceutically active agents or drugs, such as chemotherapeutic agents, for example, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, temozolomide, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc. In some embodiments, the compound or composition is administered in the form of a salt, for example, a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulfonic acids, for example, p-toluenesulfonic acid.In specific formulations, the composition comprises doxorubicin, temozolomide, and / or paclitaxel.

[0084] The active ingredients may be contained in microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. In certain embodiments, the pharmaceutical composition is formulated as an inclusion complex, as a cyclodextrin inclusion complex, or as a liposome. Liposomes can serve to target host cells (e.g., T cells or NK cells) to a specific tissue. Many methods are available for preparing liposomes, such as those described in, for example, Szoka et al. Bioeng., 9: 467 (1980) and US Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0085] The pharmaceutical composition, in some aspects, may employ slow-release, delayed-release, and sustained-release delivery systems, so that the administration of the composition occurs Petition 870260084360, dated 08 / 20 / 2026, page 43 / 79 / 70 before and with sufficient time to cause sensitization of the area to be treated. Many types of delivery systems are available and known. Such systems can avoid repeated administrations of the composition, thus increasing convenience for the subject and the physician.

[0086] The pharmaceutical composition in some embodiments contains the compound in amounts effective to treat or prevent the disease or condition, as a therapeutically effective or prophylactically effective amount to treat a disease or disorder. The therapeutic or prophylactic efficacy in some embodiments is monitored by periodic evaluation of treated individuals. For repeated administrations over many days or longer, depending on the condition, treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and may be determined. The desired dosage may be administered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. In some embodiments, continuous infusion administration may be performed using a pump.

[0087] The composition can be administered using standard administration techniques, formulations, and / or devices. Formulations and devices, such as syringes and vials, are provided for storage and administration of the compositions. Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. In some embodiments, the composition is administered parenterally. The term “parenteral,” as used in this document, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, intracranial, intrathoracic, and intraperitoneal administration. In some embodiments, the composition is administered to a subject using peripheral systemic administration by Petition 870260084360, dated 08 / 20 / 2026, page 44 / 79 / 70 intravenous, intraperitoneal or subcutaneous injection.

[0088] In some embodiments, the compositions are provided as sterile liquid preparations, for example, isotonic aqueous solutions, suspensions, emulsions, dispersions or viscous compositions, which may, in some respects, be buffered to a selected pH. Liquid preparations are normally easier to prepare than gels, other viscous compositions and solid compositions. In addition, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions may comprise carriers which may be a solvent or dispersion medium containing, for example, water, saline, phosphate-buffered saline, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof.

[0089] Sterile injectable solutions may be prepared by incorporating the linking molecule into a solvent, such as in a mixture with a suitable carrier, diluent or excipient, such as sterile water, physiological saline solution, glucose, dextrose or the like. The compositions may also be lyophilized. The compositions may contain auxiliary substances such as wetting agents, dispersants or emulsifiers (e.g., methylcellulose), pH buffering agents, gelling or viscosity-enhancing agents, preservatives, flavoring agents, colorants and the like, depending on the route of administration and the desired preparation. Standard texts may, in some respects, be consulted to prepare suitable preparations.

[0090] Various additives that improve the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, may be added. Prevention of the action of Petition 870260084360, dated 08 / 20 / 2026, page 45 / 79 / 70 The control of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the use of agents that delay absorption, for example, gelatin and aluminum monostearate.

[0091] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody in which the matrices are in the form of molded articles, for example, films or microcapsules.

[0092] The formulations to be used for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through sterile filtration membranes.

[0093] Pharmaceutical compositions for combination therapy are also provided. Any of the additional agents for combination therapy described herein may be prepared and administered as one or more pharmaceutical compositions comprising the compound. Combination therapy may be administered in one or more pharmaceutical compositions. IV. METHODS AND USES

[0094] Methods are provided here, such as methods of treatment, use and applications of the compound and / or pharmaceutical compositions and formulations thereof, such as in the treatment or prevention of a disease or disorder. Methods of combination therapy comprising the compound and / or pharmaceutical composition for the treatment or prevention of a disease or disorder are also provided. Methods for targeting tumor-associated macrophages (TAMs) are also provided. In some embodiments, the methods of use may be for targeting macrophages for the treatment of intracellular pathogens (M. tuberculosis, F. Petition 870260084360, dated 08 / 20 / 2026, p. 46 / 79 / 70 tularensis, S. typhi). In some embodiments, the method disclosed herein can be used to target tumor-associated macrophages. In some embodiments, the methods disclosed herein can be used to treat cancer. In some embodiments, the methods disclosed herein can be used to treat drug-resistant cancer, cancer cells and / or tumors (e.g., doxorubicin-resistant cancer, temolozide-resistant cancer). In some embodiments, the treatment method comprises administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE).

[0095] Methods for treating or preventing diseases or disorders related to high-expression cells of CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL) and other macrophage-related cells are provided here. These diseases or disorders may include, but are not limited to, cancer (e.g., soft tissue sarcomas or glioblastomas) or non-malignant tumors (e.g., meningiomas, hemangioblastomas, or giant cell tumors), chronic infectious diseases (e.g., tuberculosis), or a granulomatous disease (e.g., sarcoidosis). In some modalities, non-malignant tumors include, but are not limited to, meningiomas of all grades (e.g., grade 1 meningioma, grade 2 meningioma, or grade 3 meningioma), schwannomas, schwannomatosis, neurofibromas, neurofibromatosis type 1 (NF1), or neurofibromatosis type 2 (NF2).

[0096] In some modalities, cancer can be any cell in a subject undergoing unregulated growth. Cancer can be any cancer cell capable of metastasis. For example, cancer can be a sarcoma, glioma, lymphoma, leukemia, carcinoma, blastoma, or germ cell tumor. In some modalities, cancer is selected from Petition 870260084360, dated 08 / 20 / 2026, page. 47 / 79 / 70 group consisting of: carcinoma, lymphoma, blastoma, sarcoma, glioma, leukemia, lymphoid malignancies, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, squamous cell carcinoma of the esophagus, hepatocellular carcinoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, gallbladder cancer, hepatoma, breast cancer (e.g., HR+ / HER2- breast cancer, HR- / HER2- breast cancer, HR+ / HER2+ breast cancer, or HR- / HER2+ breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, glandular carcinoma salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer,Thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In some modalities, the non-malignant tumor is a meningioma, hemangioblastoma, or giant cell tumor. In certain modalities, the cancer is a brain metastasis derived from cancer. In certain modalities, the cancer is a solid tumor.

[0097] In some modalities, the cancer is a soft tissue sarcoma. In a given modality, the soft tissue sarcoma may be, but is not limited to, angiosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumors, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, undifferentiated pleomorphic sarcoma (UPS), desmoid tumor, hemangiopericytoma, fibrosarcoma, vascular sarcoma, alveolar soft tissue sarcoma (ASPS), clear cell sarcoma and soft tissue melanoma, extraskeletal myxoid chondrosarcoma (EMC), Ewing's sarcoma, or desmoplastic round cell tumors. In a modality Petition 870260084360, dated 08 / 20 / 2026, page 48 / 79 / 70 specifically, the cancer is undifferentiated pleomorphic sarcoma (UPS).

[0098] In a certain modality, the cancer is a glioma. In a certain modality, the glioma may be an astrocytoma, ependymoma, or oligodendroglioma. In certain modalities, the cancer is an astrocytoma. In a specific modality, the cancer is a glioblastoma (glioblastoma multiforme).

[0099] In a specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of soft tissue sarcoma to a subject in need. In a specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of undifferentiated pleomorphic sarcoma (UPS) to a subject in need.In one specific embodiment, the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of glioblastoma multiforme to a subject in need.

[00100] In some embodiments, the cancer, cancer cell, and / or tumor are resistant to commonly administered therapies. In some embodiments, the cancer, cancer cell, or tumor are resistant to commonly administered chemotherapeutic agents. In some embodiments, the cancer, cancer cell, and / or tumor are resistant to inhibition by doxorubicin or temozolomide. In a specific embodiment, the methods described herein comprise the administration of the compound and / or pharmaceutical composition for the treatment of a cancer resistant to Petition 870260084360, dated 08 / 20 / 2026, page 49 / 79 / 70 medications, cancer cells and / or tumors to a subject in need of it. In a specific embodiment, the methods described herein comprise the administration of the compound and / or pharmaceutical composition for the treatment of a cancer, cancer cells and / or tumor resistant to doxorubicin to a subject in need thereof. In a specific embodiment, the methods described herein comprise the administration of the compound and / or pharmaceutical composition for the treatment of a cancer, cancer cells and / or tumor resistant to temozolomide to a subject in need thereof.

[00101] In a specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of doxorubicin-resistant cancer, cancer cells and / or tumors in a subject in need. In a specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of temozolomide-resistant cancer, cancer cells and / or tumors in a subject in need.

[00102] In certain embodiments, the treatment method comprises administering an effective amount of the compound and / or pharmaceutical composition for the treatment of autoimmune diseases such as rheumatoid arthritis, lupus (SLE), or vasculitis. In certain embodiments, the treatment method comprises administering an effective amount of the compound and / or pharmaceutical composition to treat an inflammatory disease such as Crohn's disease, inflammatory bowel disease, or collagen vascular diseases. In certain embodiments, the treatment method comprises administering the compound and / or pharmaceutical composition to treat a Petition 870260084360, dated 08 / 20 / 2026, page 50 / 79 / 70 macrophage-mediated disorder.

[00103] The compositions disclosed herein may also be used to treat a lysosomal storage disease. For example, a lysosomal storage disease includes, but is not limited to, cholesterol ester storage disease, Wolman disease, Hunter syndrome, Hurler disease, Fabry disease, Gaucher disease, Krabb disease (globoid cell leukodystrophy), metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, Tay-Sachs disease, Batten disease, cystinosis, Danon disease, and Pompe disease. A. Dosage and Administration

[00104] In some embodiments, the methods disclosed herein include administration of the compound or pharmaceutical composition by any method suitable for a subject, for example, by injection, for example, intravenous or subcutaneous injections, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, subtenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral administration. In some embodiments, the compound or composition is administered parenterally, intrapulmonarily, and intranasally, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracranial, intrathoracic, or subcutaneous administration.In some embodiments, the method comprises administering the compound or pharmaceutical composition parenterally into the parenchyma or circulation, so that the disclosed compounds reach the target tissues (e.g., where cancer cells may be located). In some embodiments, the method comprises administering the compound or pharmaceutical composition directly into or adjacent to a tumor mass.

[00105] Parenteral administration of the compounds, if used, is. Petition 870260084360, dated 08 / 20 / 2026, page 51 / 79 / 70 generally characterized by injection. Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. A revised approach to parenteral administration involves the use of a slow-release or sustained-release system, so that a constant dosage is maintained.

[00106] Dosage and administration may depend in part on whether administration is brief or chronic. Various dosing regimens include, but are not limited to, single or multiple administrations at various time points, bolus administration, and pulse infusion. In some modalities, a pump may be used for sustained administration.

[00107] For the prevention or treatment of diseases, the appropriate dosage of the compound or pharmaceutical composition may depend on the type of disease being treated, the severity and course of the disease, whether the compound or pharmaceutical composition is administered for preventive or therapeutic purposes, prior therapy, the subject's medical history, and at the discretion of the attending physician. The compound or pharmaceutical composition is, in some modalities, administered appropriately to the patient all at once or over a series of treatments.

[00108] In some embodiments, a dose of the compound or composition is administered to the subject as a single dose or is administered only once within a period of two weeks, one month, three months, six months, one year or more. In some embodiments, a dose of the compound or composition is administered to the subject in multiple administrations. In some embodiments, the dose is administered to the subject once a day. In some embodiments, the dose is administered to the subject several times a day. In some embodiments, the dose is administered to the subject six times a day, five times a day, four times a day, three times a day, twice a day, once a day, on alternate days, three times a week, twice a week. Petition 870260084360, dated 08 / 20 / 2026, p. 52 / 79 / 70 week, at least once a week, once a week, once every two weeks, once every three weeks, once a month, once every two months or once every three months. In certain modalities, the dose is administered to the subject once every two weeks, once every three weeks or once a month. B. Combination Therapy

[00109] Methods of treating a disease or disorder (e.g., cancer) are also provided herein, comprising the administration of combination therapy comprising an effective amount of the compound and / or pharmaceutical composition and additional therapeutic agents or interventions to a subject in need thereof. In some embodiments, the compound and / or pharmaceutical composition is administered simultaneously with the additional therapeutic agents or interventions. In some embodiments, the compound and / or pharmaceutical composition is administered sequentially, in any order, with the additional therapeutic agents or interventions.In some embodiments, additional therapeutic agents or interventions may include, but are not limited to, chemotherapeutic agents, DNA hypomethylating agents, alkylating agents, topoisomerase inhibitors, therapeutic antibodies that bind specifically to cancer antigens, hematopoietic growth factors, cytokines, antibiotics, COX-2 inhibitors, CDK inhibitors, immunomodulators, antithymocyte globulin, immunosuppressants, corticosteroids or their pharmacological derivatives, radiation, surgery, and adjuvant therapy. In some embodiments, the compound and / or pharmaceutical composition is administered in combination with a cytotoxic or therapeutic agent. In some embodiments, the compound and / or pharmaceutical composition is administered in combination with a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises temozolomide (TMZ), doxorubicin, and / or paclitaxel. In some... Petition 870260084360, dated 20 / 08 / 2026, p. 53 / 79 / 70 modalities, the compound and / or pharmaceutical composition is administered with adjuvant therapy. In some modalities, the compound and / or pharmaceutical composition is administered with radiotherapy. In some modalities, the combination therapy comprises the compound and / or pharmaceutical composition and an additional therapeutic agent or intervention. In some modalities, the combination therapy comprises the compound and / or pharmaceutical composition and more than one additional therapeutic agent or intervention.

[00110] In a specific embodiment, the methods disclosed herein comprise administering the compound and / or pharmaceutical composition in combination with an effective amount of doxorubicin to a subject in need of it. In a specific embodiment, the methods disclosed herein comprise administering the compound and / or pharmaceutical composition in combination with an effective amount of temozolomide to a subject in need of it. In a specific embodiment, the methods disclosed herein comprise administering the compound and / or pharmaceutical composition in combination with paclitaxel to a subject in need of it. In a specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to MMAE in combination with an effective amount of doxorubicin to a subject in need of it.In one specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to MMAE in combination with an effective amount of temozolomide to a subject in need thereof. In another specific embodiment, the methods described herein comprise administering a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to MMAE in combination with... Petition 870260084360, dated 08 / 20 / 2026, page 54 / 79 / 70 an effective quantity of paclitaxel to a subject who needs it.

[00111] In some embodiments, the compound and / or pharmaceutical composition is co-administered with one or more additional therapeutic agents or in connection with another therapeutic intervention, simultaneously or sequentially in any order. In some contexts, the compound and / or pharmaceutical composition is co-administered with another therapy sufficiently close in time that the dose may enhance the effect of one or more additional therapeutic agents, or vice versa. In some embodiments, the compound and / or pharmaceutical composition is administered before one or more additional therapeutic agents. In some embodiments, the compound and / or pharmaceutical composition is administered after one or more additional therapeutic agents. V. MANUFACTURING ARTICLES OR KITS

[00112] Also provided are articles of manufacture or kits containing the compound and / or compositions comprising it. Articles of manufacture may include a container and a label or package insert on or attached to the container. Suitable containers include, for example, bottles, vials, syringes, test tubes, IV solution bags, etc. Containers may be made of a variety of materials, such as glass or plastic. In some embodiments, the container has a sterile access port. Examples of containers include IV solution bags and vials for injection, including those with needle-pierced stoppers for injection. The article of manufacture or kit may further include a package insert indicating that the compositions can be used to treat a specific condition, such as a condition described herein (e.g., cancer).Alternatively, or additionally, the manufactured article or kit may also include another or the same container comprising a pharmaceutically acceptable buffer. It may also include other materials such as other buffers, diluents, filters, needles and / or syringes. Petition 870260084360, dated 08 / 20 / 2026, page 55 / 79 / 70

[00113] The label or package insert may indicate that the composition is used to treat a disease, disorder, or condition in an individual (e.g., cancer). The label or package insert, which is on or attached to the container, may provide instructions for reconstitution and / or use of the formulation. The label or package insert may also indicate that the formulation is useful or intended for subcutaneous, intravenous, or other administration methods to treat or prevent an autoimmune disease, disorder, or condition in an individual. In some respects, the label or package insert may include instructions for use, for example, instructions for administering the compound or composition, in some respects in accordance with any of the methods or uses described herein.

[00114] The container, in some embodiments, contains a composition which, by itself or in combination with another composition, is effective in treating, preventing and / or diagnosing the condition. The manufactured article or kit may include (a) a first container with a composition contained therein (i.e., first medicament), wherein the composition includes the compound; and (b) a second container with a composition contained therein (i.e., second medicament), wherein the composition includes an additional agent, such as a cytotoxic or therapeutic agent, and which article or kit further comprises instructions on the label or package insert for treating the subject with the second medicament, in an effective amount. VI. GENERAL SYNTHETIC METHODS

[00115] Compositions of the present disclosure will now be described by reference to illustrative synthetic schemes for their general preparation below and to the specific examples that follow. Practitioners will recognize that, to obtain the various compositions in this document, starting materials may be suitably selected so that the ultimately desired substituents are carried through the reaction scheme with or without protection, as appropriate, to produce the desired product. Petition 870260084360, dated 08 / 20 / 2026, page 56 / 79 / 70 Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and substituted as appropriate with the desired substituent. Furthermore, one skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy, or side-chain groups) from reaction conditions and that such groups are removed under standard conditions when appropriate.

[00116] Chromatography, recrystallization and other conventional separation procedures can also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or otherwise purify a product of a reaction.

[00117] The general methods for preparing the compositions described herein are described in the example methods below.

[00118] In some embodiments, the compositions described herein may be synthesized according to the procedure shown in Scheme A1.

[00119] Scheme A1 Petition 870260084360, dated 08 / 20 / 2026, p. 57 / 79 / 70 Scheme A2 Step 1: Glucan

[00120] As can be seen in the schemes above, a glucan compound (such as a dextran or a cyclodextrin) reacts with an activating agent. The resulting activated glucan derivative can then react with appropriate reagents to introduce a targeting moiety coupled to the glucan backbone via a targeting ligand, as well as an active component linked to the glucan backbone via a payload ligand. A skilled craftsman will recognize that the schemes above are illustrative and that the various reagents and the order of the synthetic steps can be varied as needed to obtain the intended end products. For example, a, b, and c may each refer to Petition 870260084360, dated 20 / 08 / 2026, page 58 / 79 / 70 independently, to an integer of 0, at least 1, at least 1, from about 1 to about 165, from about 16 to about 111, from about 5 to about 167, from about 50 to about 65, or from about 6 to about 16. It should be understood that monomers of the types labeled a, b, or c may be in a block copolymer arrangement or may be randomly arranged within the polymer, or any combination thereof, unless otherwise indicated. It should also be understood that the glucan structure in the scheme above may be linear, branched, circular, or combinations thereof. Groups not specified in the schemes above, such as any terminal groups of the glucan backbone, may be any terminal groups recognizable by a specialist in the field. For example, a terminal group of the glucan backbone can be a hydroxyl terminal group of the monomer. VII. DEFINITIONS

[00121] Unless otherwise defined, all technical terms, notations, and other scientific terms or terminology used herein are intended to have the same meanings as are commonly understood by those skilled in the art to which the subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from what is generally understood in the art.

[00122] As used in this document, the singular forms “a / an”, “a / an” and “the” include the referring plural forms, unless the context clearly indicates otherwise. As used in this document, “a” or “an” means “at least one” or “one or more”. It is understood that aspects, modalities and variations described herein include “comprising” and / or “consisting of” and / or “consisting essentially of” aspects, modalities and variations. Petition 870260084360, dated 08 / 20 / 2026, p. 59 / 79 / 70

[00123] Throughout this disclosure, various aspects of the claimed matter are presented in a range format. It should be understood that the range description is simply for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the invention. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges, as well as individual numerical values ​​within that range. For example, when a range of values ​​is provided, it is understood that each intermediate value, between the upper and lower limits of that range and any other stated or intermediate value in that stated range, is covered by the claimed matter. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also covered by the claimed matter, subject to any limit specifically excluded in the stated range.When the declared range includes one or both limits, ranges that exclude either or both of those included limits are also included in the claimed subject matter. This applies regardless of the extent of the range.

[00124] The term “about”, as used in this document, refers to the usual error range for the respective value readily known to those skilled in this technical field. Reference to “about” a value or parameter includes in this document (and describes) modalities that are directed to that value or parameter, by itself. For example, the description that refers to “about X” includes the description of “X”.

[00125] As used herein, a “composition” refers to any mixture of two or more products, substances or compounds. It may be a solution, a suspension, a liquid, a powder, a paste, an aqueous solution, a non-aqueous solution or any combination thereof.

[00126] As used herein, “alkyl” refers to and includes, unless otherwise stated, a linear univalent hydrocarbon chain. Petition 870260084360, dated 20 / 08 / 2026, p. 60 / 79 / 70 saturated (i.e., unbranched) or branched or a combination thereof, having the designated number of carbon atoms (i.e., C1-C10 means from one to ten carbon atoms). Particular alkyl groups are those with 1 to 20 carbon atoms (a “C1-C20 alkyl”), with 1 to 10 carbon atoms (a “C1-C10 alkyl”), with 6 to 10 carbon atoms (a “C6-C10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[00127] As used herein, “alkylene” refers to the same residues as alkyl, but having bivalence. Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 alkylene”), having 1 to 10 carbon atoms (a “C1-C10 alkylene”), having 6 to 10 carbon atoms (a “C6-C10 alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”), or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH2-), isopropylene (-CH2CH2-).(CH3)-), butylene (CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-) and the like.

[00128] As used herein, “halo” or “halogen” refers to elements of the Group 17 series having atomic numbers from 9 to 85. Preferred halo groups include the fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted for more than one halogen, it may be referred to using a prefix corresponding to the number of halogen fractions attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl. Petition 870260084360, dated 20 / 08 / 2026, p. 61 / 79 / 70 replaced by two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen; therefore, 4-chloro-3-fluorophenyl is within the scope of di-haloaryl. An alkyl group in which each hydrogen is replaced by a halo group is called a “perhaloalkyl”. A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen occupies the place of each H in the hydrocarbon that constitutes the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[00129] As used herein, “carbamate” refers to the -OC(=O)-NH- group. Unless otherwise specified, the nitrogen atom of the carbamate group is understood to be unsubstituted (i.e., contains a hydrogen atom).

[00130] As used here, “oxo” refers to =O.

[00131] As used herein, “optionally substituted,” unless otherwise specified, means that a group may be either not substituted or substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of the substituents listed for that group, wherein the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is not substituted. VIII. EXAMPLES

[00132] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Petition 870260084360, dated 08 / 20 / 2026, pp. 62 / 79 / 70 Example 1: Structure of Target 5, a targeted chemotherapeutic agent composed of a mannosylated dextran ligand linked to the monomethyl auristatin E toxin.

[00133] A compound as described herein has been synthesized. The compound (Target 5) consists of a mannosylated dextran backbone (in order to form a mannose-binding site targeting moiety) connected by a valine-citrulline ligand to monomethyl auristatin E (MMAE). The structure of Target 5 is shown in FIG. 1. The compound in Figure 1 may also be referred to as Compound A. Synthesis of Compound A I. Synthesis of Val-Cit-PAB-MMAE pyridine, DMF

[00134] Fmoc-Val-Cit-PAB-PNP (470 mg, 0.613 mmol) in DMF (12 ml) was added pyridine (5 ml), a solution of HOBt (80 mg, 0.593 mmol) in DMF (5 ml), a solution of DIPEA (86 mg, 0.667 mmol) in DMF (5 ml) and a solution of MMAE (400 mg, 0.557 mmol) in DMF (12 ml). The mixture was stirred at room temperature for 2 days. It was diluted with EtOAc (500 ml), washed with H2O (300 ml x 5) and brine (200 ml) and dried over Na2SO4. The solution was loaded onto a silica column. It was developed with a MeOH / DCM gradient (0% to 10%) to provide Fmoc-Val-Cit-PAB-MMAE (570 mg, 0.423 mmol, 76%) as a white solid. Petition 870260084360, dated 08 / 20 / 2026, pp. 63 / 79 55 / 70 piperidine, DMF Val-Cit-PAB-MMAE Froc-Val-Crt-PAE-MMAE

[00135] To a solution of Fmoc-Val-Cit-PAB-MMAE (560 mg, 0.416 mmol) in DMF (9 ml) was added piperidine (2.3 ml). The resulting mixture was stirred at room temperature for 1 h. It was concentrated in high vacuum (water bath 20 ~ 28°C) until almost dry. EtiO (30 ml) was added. The upper solution was decanted. The residue was triturated with EtiO (20 ml x 4) and the EtiO layers were discarded. The residue was then filtered, washed with EtiO (10 ml) and dried in high vacuum to give Val-Cit-PABMMAE (409 mg, 0.364 mmol, 88%) as a white solid. II. Synthesis of mannose amine (compound 7) CbzCI, NaOH (aq.). DCM rt, 1d NHCBZ

[00136] To a mixture of amine 1 (9.00 g, 76.9 mmol) in 1 M NaOH (83.8 ml, 83.8 mmol) in an ice bath, CbzCl (14.04 g, 82.30 mmol) was added dropwise over 10 min. The ice bath was removed and the mixture was stirred for 1 h. DCM (60 ml) was added. The mixture was stirred at room temperature for 1 day. It was diluted with DCM (100 ml). The organic layer was separated, washed with brine (100 ml), dried over Na2SO4, filtered through a small silica buffer using DCM and then 1:1 DCM / EtOAc as eluents. The fractions containing products were combined and concentrated. The residue was washed with hexanes (400 ml) to give the protected amine 2 (13.50 g, 53.78 mmol, 70%) as a white solid. ACjO, pyridine ri, 2 d Petition 870260084360, dated 08 / 20 / 2026, pp. 64 / 79 56 / 70

[00137] To a solution of mannose 3 (10.00 g, 55.56 mmol) in pyridine (70 ml) was added Ac2O (30.24 g, 296.5 mmol). The mixture was stirred at room temperature for 2 days. It was added to IN HCl (1.0 L). The mixture was extracted with EtOAc (300 ml). The organic layer was washed with H2O (200 ml) and brine (200 ml), dried over concentrated NaiSOde to yield mannose pentaacetate 4 (21.65 g, 55.51 mmol, quantitative yield) as a light yellow gel.

[00138] To a solution of compound 4 (21.65 g, 55.51 mmol) in DCM (500 ml) under N2 was added compound 2 (9.50 g, 37.8 mmol) and SnCfi (15.77 g, 60.54 mmol). The mixture was stirred at room temperature for 1 day. The mixture was poured into ice-cold saturated NaHCO3 (1.2 L). It was stirred for 15 min, filtered through Celite buffer and washed with DCM (300 ml). The organic layer of the filtrate was separated. The layer was extracted with DCM (300 ml x 2). The combined organic phases were washed with brine (500 ml), dried over Na2SO4 and concentrated. The residue was purified by column chromatography using an EtOAc / DCM gradient (0% to 10%) to give compound 0 5 (6.94 g, 11.9 mmol, 32%) as a light yellow oil. MeONa. MeOH rt, 4 h

[00139] To a solution of compound 5 (6.94 g, 11.9 mmol) in MeOH (150 ml) was added 25% by weight of NaOMe in MeOH (0.85 g, 3.94 mmol). The mixture was stirred at room temperature for 4 h. Amberlite IR 120 (H) resin (5.50 g) was added to adjust pH 0 to ~6. The mixture Petition 870260084360, dated 08 / 20 / 2026, pp. 65 / 79 57 / 70 was filtered. The filtrate was concentrated to give compound 6 (4.80 g, 11.6 mmol, 98%) as a colorless oil. Pd / C. AcOH. Hzrt, 5 h

[00140] A solution of compound 6 (4.80 g, 11.6 mmol) in MeOH (200 ml) was purged with N2 for 15 minutes. Pd / C (10% by weight, 1.30 g) was added. The mixture was evacuated and recharged with H2. An H2 bottle was connected and the mixture was stirred at room temperature for 5 h. It was filtered, washed with MeOH (100 ml). The filtrate was concentrated and dried under high vacuum to give mannose (quantitative amine) as a yellow oil. III. Synthesis of Compound A (3.24 g, 11.6 mmol, yield & Dextran MW -60000HOH o2n

[00141] To a solution of dextran 8 (Mw -6000, 2.00 g, 12.3 mmol glucose units) in DMSO (60 ml) pyridine (60 ml) was added. The mixture was cooled in an ice water bath. Compound 9 (2.48 g, 12.3 mmol) and DMAP (250 mg, 2.05 mmol) were added. The mixture was stirred at 4°C for 4 h. EtOH (600 ml) was added. The mixture was left to stand at room temperature for 10 min. It was filtered, washed with EtOH (100 ml), E2O (100 ml) and dried under high vacuum to yield compound 10 (2.20 g, -22 mol% carbonate per mol glucose units by 1H NMR). The average molecular weight of a repeating unit is approximately 198 g / mol. Petition 870260084360, dated 08 / 20 / 2026, pp. 66 / 79 58 / 70 Target 5-6k

[00142] A solution of compound 10 (930 mg, 1.03 mmol carbonates) was added to a solution of HOBt (148 mg, 1.10 mmol) in DMSO (5.0 ml), a solution of DIPEA (148 mg, 1.15 mmol) in pyridine (8.4 ml), and a solution of Val-Cit-PAB-MMAE (232 mg, 0.207 mmol) in DMSO (12.0 ml). The mixture was stirred at room temperature for 90 min. Then, a solution of mannose amine 7 (232 mg, 0.832 mmol) in DMSO (5.0 ml) was added. The mixture was stirred at room temperature for 20 h. EtOH (500 ml) was added. The mixture was allowed to settle at room temperature for 2 h. It was filtered, washed with EtOH (200 ml) and dried under high vacuum to give Target 5-6k (900 mg) as a white solid. By Ή, NMR, for one mole of glucose units, the compound contains 3.1 mol% of MMAE and 11.6 mol% of mannose (and as the polymer has 37 glucose units on average, it has 1 unit of MMAE and 4 units of mannose).The average molecular weight of a repeating unit is approximately 234 g / mol and the Mw is approximately 8600. Example 2: Administration of Target 5 demonstrates strong anticancer efficacy in multiple murine soft tissue sarcoma (STS) tumor models. Subcutaneous Model

[00143] The anticancer efficacy of Target 5 was determined in an HT1080 mouse subcutaneous fibrosarcoma model. Briefly, 7-8 week old female naked athymic mice (strain code 490; Charles River Laboratories) were subcutaneously inoculated with HT1080 cells (at 1 χ²¹⁰⁶ cells / animal) in the right flank region. Tumors were allowed to grow to 150 mm³ before initiation. Petition 870260084360, dated 08 / 20 / 2026, pp. 67 / 79 / 70, regarding the dosage of Target 5. Tumors were measured in length and width in millimeters three times a week. Tumor volumes were calculated using the formula V = L x W x W / 2. If a second tumor occurred in a given animal, both tumor volumes were measured and their volumes were added together. Target 5 was administered twice a week via the lateral tail vein at 5 mg / kg or 10 mg / kg. Saline solution was administered via the tail vein and doxorubicin (4 mg / kg) was injected intraperitoneally.

[00144] As seen in Figure 2, Target 5 was able to reduce tumor volume in a dose-dependent manner. Mice that received 10 mg / kg of Target 5 showed decreased tumor volume comparable to mice treated with doxorubicin (FIG. 2A). Based on the stable weight gain of the mouse, there is no significant toxicity of Target 5; however, administration of doxorubicin causes significant toxicity, as illustrated by the decrease in body weight (FIG. 2B). Intracranial Model

[00145] The therapeutic effect of Target 5 was analyzed in a highly aggressive STS brain metastasis model. HT1080 cells expressing luciferase (HT1080-Luc) were implanted intracranially on day 0. On day 4, mice were included in treatment groups with equivalent mean tumor size, as determined by mean bioluminescence intensities. Mice received saline or 10 mg / kg of Target 5 on days 4 and 7 and underwent imaging on day 10. As shown in FIG. 3, mice that received Target 5 (right panels) demonstrated a marked reduction in tumor volume (as determined by a visible reduction in bioluminescence) after two doses, compared to mice that received saline (left panels), where the Petition 870260084360, dated 08 / 20 / 2026, pp. 68 / 79 / 70. Tumors increased in size. The reduction in tumor volume in mice treated with Target 5 was statistically significantly different from mice treated with saline solution, as determined by 2-way ANOVA p<0.0001. Although STS rarely metastasizes to the brain, these data show that administration of Target 5 would be effective in these cases and suggest a potential broader applicability for the administration of Target 5 in primary CNS tumors and CNS metastases from other types of cancer. PDX Model of Doxorubicin-Resistant Undifferentiated Pleomorphic Sarcoma (UPS)

[00146] The efficacy of Target 5 was determined in a UPS PDX model (Certis Oncology Solutions PDX model CRT00001.001 (an undifferentiated pleomorphic sarcoma resistant to doxorubicin). UPS is a doxorubicin-resistant subtype of STS. Nude male and female mice (n=8 for each group) were implanted with tumor fragments (CRT0000.001) subcutaneously in the right hind flank. When the tumors reached a range of 72-294 mm3 with a mean of 150 mm3, the mice were randomized to their respective treatment groups and received doses within 24 hours. Target 5 is administered intravenously using 2 mg / kg; 4 mg / kg, 8 mg / kg or 10 mg / kg dosed twice weekly. Control mice were given intravenous saline twice weekly. Tumor volume and Body weight was measured twice a week. The mice were monitored and dosed for up to 14 days, until the animals reached a tumor volume of 1.500 mm3, or the human endpoint, whichever occurred first. As seen in FIG. 4A and FIG. 4B, Target 5 exhibited a dose-dependent tumor suppressor effect in a PDX model of doxorubicin-resistant sarcoma. Mice receiving 4 mg / kg, 8 mg / kg, and 10 mg / kg of Target 5 demonstrated nearly equivalent reductions in tumor volume. Petition 870260084360, dated 08 / 20 / 2026, pp. 69 / 79 / 70, indicating a broad therapeutic index for Target 5. The average body weight of the mice was comparable between each treatment group.

[00147] At the end of the study, the complete blood count (CBC) and blood biochemistry of the PDX CRT0000.001 model were determined. The values ​​indicate the average of four mice (randomly selected) from the control groups with saline solution, 4 mg / kg Target 5 and 10 mg / kg Target 5. Comparison of the mean analyte values ​​between the treatment groups demonstrates broad tolerability to Target 5, even at the highest dose. Table 1: CBC Panels and Chemistry____________________________________ Hemoglobin (average) Saline=13.8 RS-5 (4 mg / kg)=13.5 RS-5 (10 mg / kg)=12.5 Alk Phos (average) Saline=90 RS-5 (4 mg / kg)=89 RS-5 (10 mg / kg)=90 BUN / Cre (average) Saline=19 / 0 RS-5 (4 mg / kg)=22 / 0 RS-5 (10 mg / kg)=20 / 0 WBC (average) Saline=3.9 RS-5 (4 mg / kg)=3.5 RS-5 (10 mg / kg)=3.4 AST / ALT (average) Saline=77 / 29 RS-5 (4 mg / kg)=78 / 32 RS-5 (10 mg / kg)=88 / 30 LDH (average) Saline=1071 RS-5 (4 mg / kg)=492 RS-5 (10 mg / kg)=677 Platelets (average) Saline=1068 RS-5 (4 mg / kg)=886 RS-5 (10 mg / kg)=1660 Amylase / Lipase (average) Saline=508 / 46 RS-5 (4 mg / kg)=569 / 49 RS-5 (10 mg / kg)=716 / 54 Total Bilirubin (average) Saline 0.15 mg / dl RS-5 (4 mg / kg) 0.125 mg / dl RS-5 (10 mg / kg) 0.15 mg / dl Glucose (average) Saline=174 RS-5 (4 mg / kg)=150 RS-5 (10 mg / kg)=148 Albumin (average) Saline=2.4 RS-5 (4 mg / kg)=2.6 RS-5 (10 mg / kg)=2.9 Total Protein (average) Saline 4.65 g / dl RS-5 (4 mg / kg) 4.82 g / dl RS-5 (10 mg / kg) 5.2 g / dl

[00148] Forty-five (45) female nude mice were implanted with tumor fragments subcutaneously in the right hind flank. When the tumors reached a range of 72-294 mm3 with an average of 150 mm3, 30 mice were randomized to the respective treatment groups and received doses within 24 hours. Target 5 is administered intravenously using 10 mg / kg dosed twice weekly. Control mice were given intravenous saline twice weekly. Tumor volume and body weight were measured twice weekly. Mice were monitored and dosed for up to 26 days, until the animals reached a tumor volume of 1,500 mm3, or the human endpoint, whichever occurred first. At the end of the study, or when the Petition 870260084360, dated 08 / 20 / 2026, pp. 70 / 79 / 70 animals reached the human endpoint, 3-4 tumors per group were resected and processed as FFPE. FIG. 4C shows that Target 5 administered at 10 mg / kg per dose shows strong anticancer efficacy and was more effective in controlling tumor growth than doxorubicin in this doxorubicin-resistant model. End-of-study dissections of representative tumors are shown in FIG. 4D. These data show that Target 5 is therapeutically effective in treating doxorubicin-resistant cancer. Example 3: Administration of Target 5 demonstrates strong anticancer efficacy in mouse glioma models. Subcutaneous Glioma Model

[00149] To determine the anticancer efficacy of Target 5 in a glioma model, eight groups of athymic mice (n=8 for each group) were implanted with a human glioma cell line (U87MG) on day 0. Mice received various doses of Target 5, saline solution, or temozolomide (12.5 mg / kg) twice weekly, starting on day 14 (when tumor volume is approximately 100 mm3). Temozolomide administration is currently the standard of care. Target 5 was administered to mice intravenously, while temozolomide was administered by oral gavage. Figure 4 shows that Target 5 was able to reduce tumor volume in a dose-dependent manner (FIG. 5A), without exhibiting significant toxicity, as determined by an impact on mouse body weight (FIG. 5B). Temozolomide-Resistant Glioma Model

[00150] The efficacy of the therapeutic effect of Target 5 in a moderately temozolomide-resistant tumor was analyzed. Five groups of immunocompetent mice (C57BL / 6; n=10 per group; Jackson Laboratories) were subcutaneously implanted with 5 x 10⁶ GL261 tumor cells on day 0. GL261 tumor cells are moderately resistant to temozolomide chemotherapy. The mice were Petition 870260084360, dated 08 / 20 / 2026, page 71 / 79 / 70 administered saline, temozolomide (12.5 mg / kg by gavage) or various concentrations of Target 5 (5 mg / kg, 7.5 mg / kg or 10 mg / kg by injection into the tail vein). Figure 5 shows the effect of Target 5 on GL261 tumor volume. On day 21, mean vehicle-treated tumor volume = 1687 mm3, SD = 928.9 mm3; Mean 5 mg / kg Target 5-treated tumor volume = 440.5 mm3, SD = 159.2 mm3; Mean 7.5 mg / kg Target 5-treated tumor volume = 275.1 mm3, SD = 120.7 mm3; Mean tumor volume treated with Target 5 (10 mg / kg) = 117.2 mm3, SD = 89.6 mm3; Mean tumor volume treated with temozolomide = 302.6 mm3; SD = 99.7. These data show that the protection provided by Target 5 is greater than the protection provided by temozolomide, the standard chemotherapeutic agent used to treat glioblastoma. Target 5 was able to reduce tumor volume in a dose-dependent manner (FIG. 6A), without having a detrimental effect on the weight of the mice (FIG. 6B).Furthermore, representative tumors dissected at the end of the study illustrate the reduced tumor volume in mice administered with Target 5 compared to mice treated with saline (FIG. 6C). These data show that administration of Target 5 is capable of exerting strong antitumor efficacy in a moderately resistant tumor without any appreciable toxicity. Example 4: Efficacy of Target 5 in inhibiting the growth of temozolomide-resistant tumors in an immunocompetent intracranial glioma model.

[00151] In this exemplary method, the ability of Target 5 to reach the blood-brain barrier is determined and the anticancer efficacy of a temozolomide-resistant tumor is demonstrated in an immunocompetent intracranial glioma model.

[00152] In this exemplary method, fifty-five C57B / 6 mice (including surplus) are acquired (equal numbers of males and females). The mice are 8 weeks old at the time of... Petition 870260084360, dated 08 / 20 / 2026, pp. 72 / 79 / 70 implantation and weigh > 20 g at the time of implantation to ensure they have adequate reserve for planned interventions. Recognizing the potential immunogenicity of GL261 luciferase cell lines (Sanchez et al., 2020), the non-transgenic GL261 model is used and anticancer efficacy is evaluated through a Kaplan-Meier (KM) survival study. Low-passage GL261 cells (ATCC) are expanded and 5X104 cells in 2 mL are stereotaxically implanted into the brain. Any mouse with obvious cell leakage through the trepanation hole is excluded. Based on body weight, mice are distributed (n=10 / group) into four test groups: control with saline solution twice a week, target 5 to 10 mg / kg twice a week and 6.75 mg / kg 3 times a week, and temozolomide at 10 mg / kg 2 times a week. All treatments are administered by intravenous injection into the caudal vein starting on day 6 after implantation.Body weights are collected 3 times a week for 4 weeks. Mice are carefully monitored and euthanized when they meet the criteria for euthanasia (see Vertebrate Animals section).

[00153] After the study is completed, KM survival data are calculated, and brains from healthy and moribund mice (but not dead mice) are collected for assessment of differences in tumor size, followed by sectioning, hematoxylin staining, and IHC against CD206 at a 1:500 dilution (Abcam ab64693, Cambridge, UK) to assess CD206 expression in this intracranial model. Blood is collected for analysis, including complete blood count, reticulocyte count, and chemical tests to identify signs of hepatic, renal, or hematological toxicity. Quantitative IHC is performed against P-glycoprotein (Pgp), the gene product of MDR1.

[00154] All in vivo studies are conducted with 10 mice per group and performed in a blinded manner. For each group, data (body weight and survival) are collected from individual mice. Differences Petition 870260084360, dated 08 / 20 / 2026, pp. 73 / 79 / 70 statistically significant by two-tailed t-tests of equal / unequal variance are applied to the data comparing the control group to the groups that received test articles, and the p-values ​​are determined. Example 5: Efficacy of Target 5 in inhibiting the growth of temozolomide-resistant tumors in a PDX glioma model.

[00155] In this exemplary method, the efficacy of Target 5 in a PDX glioma model is determined. A PDX model based on high IC-50 temozolomide and MGMT methylation status is selected. Emphasis is placed on selecting models derived from patients with and without prior treatment. Pilot studies using subcutaneous and intracranial implantation of the selected PDX lines in athymic mice to establish a predictive growth curve for subsequent studies are performed. Tumor size is measured twice weekly with calipers for subcutaneous tumors and by magnetic resonance imaging for intracranial tumors.

[00156] Once the growth curve for temozolomide-resistant PDX lines in athymic mice has been established, subcutaneous anticancer efficacy studies are conducted using Target 5 in both PDX models. When >40 animals per PDX model have tumors measuring 120-200 mm3 by caliper measurements, the animals are randomized and placed into study groups.

[00157] Target 5 is administered intravenously using 5 mg / kg twice weekly; 10 mg / kg twice weekly; or 6.7 mg / kg three times weekly. Rats treated with temozolomide receive temozolomide at a dose of 10 mg / kg twice weekly, and control rats receive intravenous saline solution twice weekly. Animals remain in the study until they reach moribundity, death, or a tumor volume of 31500 mm3. The antitumor effect of Target 5 on temozolomide-resistant tumors in a PDX model is evaluated.

[00158] A dosage regimen, selected based on the efficacy of Target 5 in the subcutaneous model, is developed for an intracranial study. Petition 870260084360, dated 08 / 20 / 2026, pp. 74 / 79 / 70 using PDX models. Forty-five (45) athymic mice per model (1.5X above the age, equal number of males and females) are weighed 3x / week and tumor volume is measured once a week by MRI. Volumetric measurements of tumor size are determined by magnetic resonance imaging, rather than relying on the more commonly used 2D measurements. When > 30 animals present tumors measuring > 5 mm3, the mice are randomized and placed in the study. Mice remain in the study using moribundity or death as outcomes. Data include KM survival curves and tumor volumetry. For each group, data are analyzed for mean, median (with standard deviation and error), as well as for individual mice within each group. Statistically significant differences are determined using two-tailed t-tests with equal / unequal variance applied to the entire dataset, and p-values ​​are determined.

[00159] Data from these studies are used to evaluate the anticancer efficacy of Target 5 as an effective single therapeutic agent in patients with glioblastoma who have or develop resistance to temozolomide. Example 6: Efficacy of target 5 in inhibiting the growth of the doxorubicin-resistant UPS PDX model.

[00160] In this exemplary method, the anticancer effect of Target 5 is determined in a second UPS PDS model. In this study, Target 5 is administered intravenously at 10 mg / kg and doxorubicin at 2 mg / kg twice weekly. A saline control and a Target 5 without MMAE (10 mg / kg twice weekly) are also administered. The administered dose of doxorubicin provides anticancer efficacy without dose-limiting toxicity. Cryopreserved tumor fragments are implanted in the right flank as above (n=10 / group, total of 60 mice, 1.5X older, equal number of males and females). When Petition 870260084360, dated 08 / 20 / 2026, pp. 75 / 79 / 70 the tumors reach 120-200 mm3 according to caliper measurements, the animals are randomized and placed into study groups and monitored as described above.

[00161] All in vivo studies are performed in a blinded manner, using a sufficient number of mice per group to be statistically significant. For each group, data are analyzed for mean, median (with standard deviation and error), as well as for individual mice within each group. Statistically significant differences using two-tailed t-tests of equal / unequal variance are applied to the data comparing the vehicle control group to the groups that received the test article, and p-values ​​are determined. Example 7: Efficacy of target 5 in inhibiting synovial sarcoma, leiomyosarcoma, and Ewing / PNET.

[00162] In this exemplary method, the efficacy of Target 5 in PDX models of STS subtypes with strong CD206 expression is evaluated. Anticancer efficacy studies are performed as described above; n=10 / group (saline solution, Target 5, doxorubicin) with equal numbers of male and female mice. At the end of the study, hematological and chemical panels and necropsy are performed on a subset of mice in each PDX study. At least one study includes satellite PK animals for evaluation of exposure to Target 5 and MMAE in plasma and tissues (tumor, brain, heart, liver, kidneys, and gastrointestinal tract). Example 8: Determination of MMAE in systemic circulation in mice after administration of Target 5

[00163] The amount of free MMAE in the systemic circulation of normal, tumor-free mice was determined after administration of Target 5. Seven groups of female CD-1 mice (n=3 for each time point) received 10 mg / kg of Target 5 intravenously as a single dose at Time 0. At the designated time points (0h, 0.5h, 1h, 2h, 4h, 8h, and 24h), the Petition 870260084360, dated 08 / 20 / 2026, pp. 76 / 79 / 70 mice were sacrificed and the plasma concentration of free MMAE was determined. Table 2: Free MMAE in circulation _____________________________ Analyte t1 / 2 Co AUCinf Vss Cl (h) (ng / mL) (h*ng / mL) (mL / kg) (mL / h / kg) Target 5 Mean 5.6 79440 44297 773 230 CV% 19.5 38.5 16.5 35.8 16.5 MMAE of Target 5 Mean 7.5 8.6 72 na na CV% 20.8 16.8 18.5 na na

[00164] As shown in FIG. 7, the pharmacokinetics of Target 5 are characterized by high exposure (C0 and AUCinf), very low clearance (Cl), moderate volume of distribution (Vss), long half-life (t1 / 2), and low variability. These data show that very little free MMAE is present in the circulation of mice (0.2%). Example 9: Anticancer efficacy of target 5 in a murine model of PDX sarcoma (CRT0028.001)

[00165] The anticancer efficacy of Target 5 in a second PDX model (CRT0028.001; an untreated undifferentiated pleomorphic sarcoma) was examined. Seventeen (17) athymic mice (males and females) were subcutaneously implanted with CRT00288.001, an undifferentiated pleomorphic sarcoma (Certis Oncology Solutions, San Diego). On a rolling basis, when tumors measured 120-150 mm3, mice were randomized into three groups and received 2x / week doses of saline solution as vehicle control, 10 mg / kg of Target 5 or 1 mg / kg of doxorubicin.

[00166] FIG. 8A shows the mean tumor volumes for each group as a function of the study day. The figure illustrates that 10 mg / kg of Target 5 exhibits greater antitumor efficacy than 1 mg / kg of doxorubicin. FIG. 8B shows that mice treated with 10 mg / kg of Target 5 demonstrated stable body weight, a broad indicator of health and a measure of tolerability for Target 5. Example 10: CD206 engagement in the absence of MMAE Petition 870260084360, dated 08 / 20 / 2026, pp. 77 / 79 / 70

[00167] The effect of Target 5 without MMAE was evaluated. FIG. 9 shows the effect of saline solution, Compound B (Target 5 without MMAE), and Target 5 on tumor volume in GL261-bearing mice. Wild-type C57BL / 6 mice (12 males and 12 females) were subcutaneously implanted with 5 x 10⁶ cells of the GL261 glioma cell line. When tumors reached an average of 102 mm³, mice were randomized into 3 treatment groups: saline control, 10 mg / kg Compound B, and 9 mg / kg Target 5 (equivalent molar concentrations of each test group) and dosed twice weekly for 18 days. Two-way ANOVA was performed using GraphPad Prism 9.0, adjusted for column effects in the main column. *P<0.05; **P<0.001. TGI = Total Growth Inhibition. As seen in FIG. 9A, Compound B does not demonstrate anticancer efficacy, while Target 5 demonstrates strong antitumor activity.

[00168] FIG. 9B depicts representative examples of GL261 tumors excised at the end of the study from mice treated with saline, treated with Compound B (10 mg / kg), and treated with Target 5 (9 mg / kg). Doses of Compound B and Target 5 are molar equivalent. Tumors were immunostained with anti-CD206 (Cell cat# 24595S Dilution: 1:1600). The upper left box in each panel shows a dissected tumor at the end of the study. As observed in FIG. 9B, mice treated with Target 5 showed a marked reduction in tumor size compared to mice treated with Compound B, and strong CD206 expression, indicating an absence of downregulation of CD206 expression with Target 5 treatment. Example 11: Anticancer efficacy of Target 5 in a murine model of PDX myxofibrosarcoma.

[00169] The anticancer efficacy of Target 5 in a PDX model of sarcoma (myxofibrosarcoma) was examined. Twenty-one (21) athymic male mice were implanted with tumor fragments. Petition 870260084360, dated 08 / 20 / 2026, pp. 78 / 79 / 70 subcutaneously in the right hind flank. Mice were randomized into three groups and received 2x / week doses of saline solution as a control vehicle, 10 mg / kg of Target-5, or 1 mg / kg of doxorubicin. As shown in FIG. 10, mice treated with Target 5 showed smaller tumor volume than mice treated with saline solution or doxorubicin in this model. These data indicate that Target 5 exhibits anticancer efficacy in a PDX model of myxofibrosarcoma. Petition 870260084360, dated 08 / 20 / 2026, page 79 / 79

Claims

1 / 14 CLAIMS 1. A method for treating cancer in a subject, the method characterized in that it comprises administering to the subject having the cancer, a composition comprising a compound comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting fraction to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain fraction and wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the tumor-associated macrophage targeting fraction.

2. Method according to claim 1, characterized in that the plurality of backbone monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic linkage or a beta-1,4 glycosidic linkage.

3. Method according to claim 1 or 2, characterized in that the plurality of D-glucose monomers is n, where n = 5 to 167.

4. Method according to any one of claims 1 to 3, characterized in that the plurality of D-glucose monomers is n, where n = 50 to 65.

5. Method according to any one of claims 1 to 4, characterized in that the glucan backbone is a linear dextran molecule. Petition 870250074096, dated 21 / 08 / 2025, p. 80 / 108 2 / 14 6. Method according to any one of claims 1 to 4, characterized in that the glucan backbone is a cyclodextrin molecule, wherein n=6 to 16.

7. A method according to any one of claims 1 to 6, characterized in that the tumor-associated macrophage targeting fraction comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or fragments thereof, or chondroitin sulfate.

8. Method according to any one of claims 1 to 7, characterized in that the targeting fraction is a mannose.

9. Method according to claim 8, characterized in that the ratio of mannose to backbone monomers is from about 1 to 5 to about 1 to 33.

10. Method according to claim 8 or 9, characterized in that the ratio of mannose to backbone monomers is from about 1 to 6 to about 1 to 19.

11. A method according to any one of claims 1 to 7, characterized in that the degree of mannose substitution in a cyclodextrin varies from about 0.1 to about 7.

12. A method according to any one of claims 1 to 8 or 11, characterized in that the degree of mannose substitution in a cyclodextrin varies from about 0.5 to about 5.

13. A method according to any one of claims 1 to 12, characterized in that the targeting ligand is connected to the glucan backbone via the oxygen atom of the carbamate group.

14. Method according to any one of claims 1 to 13, characterized in that the chain fraction of the targeting ligand comprises a C3-C7 alkylene chain.

15. Method according to any one of claims 1 to 14, characterized in that the chain fraction of the targeting ligand comprises a C6-alkylene fraction.

16. Method according to any one of claims 1 to 15, characterized in that the chain fraction of the targeting ligand comprises an unsubstituted C6-alkylene fraction.

17. Method according to any one of claims 1 to 16, characterized in that the carbon atom of the carbamate group of the targeting ligand is the only sp2 hybridized carbon when said ligand is attached to mannose.

18. Method according to any one of claims 1 to 17, characterized in that the tumor-associated macrophage targeting fraction is a fraction targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180) or CD301 (MGL).

19. Method according to claim 18, characterized in that the tumor-associated macrophage targeting fraction is a CD206 targeting fraction.

20. Method according to any one of claims 1 to 19, characterized in that the compound has a molar ratio between the TAM targeting fraction and the active component of about 1:1 to about 1:

10.

21. Method according to any one of claims 1 to 20, characterized in that the molar ratio between the targeting fraction of TAM and the active component is about 1:1, about 1:2 or about 1:

3.

22. Method according to any one of claims 1 to 21, characterized in that the active component is coupled to the dorsal spine of glucan by means of a payload linker.

23. Method according to any one of claims 1 to 22, characterized in that the active component is a cytotoxic agent.

24. Method according to claim 23, characterized in that the cytotoxic agent is selected from the group consisting of auristatin, dolastatin, auristatin E, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), dimethylvaline-valinadolaisoleuin-dolaproin-phenylalanine-p-phenylenediamine (AFP), auristatin E ester of 5-benzoylvaleric acid (AEVB), auristatin EB (AEB), ansamitocin, ivlertansine / emtansine (DMI), ravtansine / soravtansine (DM4), duocarmycins, calicheamicins and pyrrolobenzodiazepines.

25. Method according to claim 24, characterized in that the cytotoxic agent is MMAE.

26. Method according to claim 22, characterized in that the payload binder is a non-cleavable binder.

27. Method according to claim 26, characterized in that the payload linker comprises a carbamate group and a chain fragment, wherein the carbamate group is connected to the backbone monomer and the chain fragment connects the carbamate group and the active component.

28. Method according to claim 22, characterized in that the payload binder is a cleavable binder.

29. Method according to claim 28, characterized in that the cleavable ligand is capable of being cleaved by a protease.

30. Method according to claim 29, characterized in that the protease is either a lysosomal protease or an endosomal protease.

31. Method according to claim 28, characterized in that the cleavable ligand is capable of being cleaved by a change of pH.

32. Method according to claim 28, characterized in that the payload binder comprises a Val-Cit fraction.

33. A method according to any one of claims 1 to 32, characterized in that the cancer is a solid tumor selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, glioma, leukemia, lymphoid malignancies, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, gallbladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

34. Method according to claim 33, characterized in that the solid tumor is a sarcoma or glioblastoma.

35. Method according to claim 34, characterized in that the cancer is a soft tissue sarcoma.

36. Method according to claim 35, characterized in that the cancer is undifferentiated pleomorphic sarcoma (UPS).

37. Method according to any one of claims 1 to 36, characterized in that the subject and / or cancer (a) is resistant to temozolomide (TMZ) and / or doxorubicin and / or (b) comprises a population of cells that are resistant to inhibition by TMZ and / or doxorubicin.

38. Method according to any of the claims 1 Petition 870250074096, dated 21 / 08 / 2025, p. 84 / 108 6 / 14 to 37, characterized in that the composition is administered to the subject six times a day, five times a day, four times a day, three times a day, twice a day, once a day, on alternate days, three times a week, twice a week, at least once a week, once a week, once every two weeks, once every three weeks, once a month, once every two months or once every three months.

39. Method according to claim 38, characterized in that the composition is administered to the subject once every two weeks, once every three weeks, or once a month.

40. A method according to any of claims 1 to 39, characterized in that the method further comprises administering one or more additional therapeutic agents, adjuvant therapy and / or radiation therapy to the subject.

41. Method according to claim 40, characterized in that one or more additional active agents are selected from the group consisting of chemotherapeutic agents, DNA hypomethylating agents, alkylating agents, topoisomerase inhibitors, therapeutic antibodies that bind specifically to cancer antigens, hematopoietic growth factors, cytokines, antibiotics, cox-2 inhibitors, CDK inhibitors, immunomodulators, antithymocyte globulin, immunosuppressants and corticosteroids or pharmacological derivatives thereof.

42. Method according to claim 41, characterized in that one or more additional active agents are a chemotherapeutic agent.

43. Method according to claim 42, characterized in that the chemotherapeutic agent is TMZ, doxorubicin and / or paclitaxel.

44. Method according to any of the claims in Petition 870250074096, dated 08 / 21 / 2025, page 85 / 108 7 / 14 43, characterized in that the chemotherapeutic agent is administered before, simultaneously and / or after the start of administration of the composition to the subject.

45. Method according to claim 40, characterized in that adjuvant therapy and / or radiotherapy is administered before, simultaneously with, and / or after the start of administration of the composition to the subject.

46. ​​A method according to any one of claims 1 to 45, characterized in that the composition is administered to the subject intravenously, intraperitoneally, subcutaneously, intramuscularly, intracranially, or by infusion pump.

47. Method according to claim 46, characterized in that the composition is administered intravenously or by pump infusion to the subject.

48. Method for treating glioblastoma in a subject, the method characterized in that it comprises administering to the subject having glioblastoma a composition comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting fraction to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain fraction and wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the tumor-associated macrophage targeting fraction, wherein Petition 870250074096, dated 08 / 21 / 2025, p.86 / 108 8 / 14 the subject and / or the glioblastoma (a) is resistant to TMZ and / or (b) comprises a population of cells that are resistant to inhibition by TMZ.

49. Method for treating brain metastases in a subject, the method characterized in that it comprises administering to the subject having brain metastases a composition comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan backbone;and iv) a targeting ligand that links the targeting moiety to the glucan backbone, wherein the targeting ligand comprises a carbamate group and a chain moiety and wherein the carbamate group is connected to the backbone monomer and the chain moiety connects the carbamate group and the targeting moiety of tumor-associated macrophages, wherein the subject and / or the brain metastases (a) are resistant to TMZ and / or (b) comprise a population of cells that are resistant to inhibition by TMZ.

50. Method for treating UPS in a subject, the method characterized by the fact that it comprises administering to the subject having UPS a composition comprising: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component comprising MMAE, wherein Petition 870250074096, dated 08 / 21 / 2025, p.87 / 108 9 / 14 active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety and wherein the carbamate group is connected to the backbone monomer and the chain moiety connects the carbamate group and the targeting moiety of tumor-associated macrophages, wherein the subject and / or UPS (a) is doxorubicin resistant and / or (b) comprises a population of cells that are doxorubicin resistant.

51. A method according to any one of claims 48 to 50, characterized in that the plurality of backbone monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic linkage or a beta-1,4 glycosidic linkage.

52. Method according to any one of claims 48 to 51, characterized in that the plurality of D-glucose monomers is n, where n = 5 to 167.

53. Method according to any one of claims 48 to 52, characterized in that the plurality of D-glucose monomers is n, where n = 50 to 65.

54. Method according to any one of claims 48 to 53, characterized in that the glucan backbone is a linear dextran molecule.

55. Method according to any one of claims 48 to 53, characterized in that the glucan backbone is a cyclodextrin molecule, wherein n=6 to 16.

56. Method according to any one of claims 48 to 55, characterized in that the tumor-associated macrophage targeting fraction comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or fragments thereof, or chondroitin sulfate.

57. Method according to any one of claims 48 to 56, characterized in that the targeting fraction is a mannose.

58. Method according to claim 57, characterized in that the ratio of mannose to backbone monomers is from about 1 to 5 to about 1 to 33.

59. Method according to claim 57 or 58, characterized in that the ratio of mannose to backbone monomers is from about 1 to 6 to about 1 to 33.

60. Method according to any one of claims 48 to 56, characterized in that the degree of mannose substitution in a cyclodextrin varies from about 0.1 to about 7.

61. Method according to any one of claims 48 to 57 or 60, characterized in that the degree of mannose substitution in a cyclodextrin varies from about 0.5 to about 5.

62. A method according to any one of claims 1 to 61, characterized in that the targeting ligand is connected to the glucan backbone via the oxygen atom of the carbamate group.

63. Method according to any one of claims 1 to 62, characterized in that the chain fraction of the targeting ligand comprises a C3-C7 alkylene chain.

64. Method according to any one of claims 1 to 63, characterized in that the chain fraction of the targeting ligand comprises a C6-alkylene fraction.

65. Method according to any one of claims 1 to 64, characterized in that the chain fraction of the targeting ligand comprises an unsubstituted co-alkylene fraction.

66. A method according to any one of claims 1 to 65, characterized in that the carbon atom of the carbamate group of the targeting ligand is the only sp2 hybridized carbon when said ligand is attached to mannose.

67. Method according to any one of claims 1 to 66, characterized in that the tumor-associated macrophage targeting fraction is a fraction targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180) or CD301 (MGL).

68. Method according to claim 67, characterized in that the tumor-associated macrophage targeting fraction is a CD206 targeting fraction.

69. Method according to any one of claims 48 to 68, characterized in that the compound has a molar ratio between the TAM targeting fraction and the active component of about 1:1 to about 1:

10.

70. Method according to any one of claims 48 to 69, characterized in that the molar ratio between the targeting fraction of TAM and the active component is about 1:1, about 1:2 or about 1:

3.

71. A method according to any one of claims 48 to 70, characterized in that the active component is coupled to the glucan backbone by means of a payload linker.

72. Method according to claim 71, characterized in that the payload binder is a non-cleavable binder.

73. Method according to claim 72, characterized in that the payload linker comprises a carbamate group and a chain fragment, wherein the carbamate group is connected to the backbone monomer and the chain fragment connects the carbamate group and the active component.

74. Method according to claim 71, characterized in that the payload binder is a cleavable binder.

75. Method according to claim 74, characterized in that the cleavable ligand is capable of being cleaved by a protease.

76. Method according to claim 75, characterized in that the protease is either a lysosomal protease or an endosomal protease.

77. Method according to claim 74, characterized in that the cleavable ligand is capable of being cleaved by a change in pH.

78. Method according to claim 74, characterized in that the payload binder comprises a Val-Cit fraction.

79. A method according to any one of claims 48 to 78, characterized in that the method further comprises administering radiation therapy to the subject.

80. Method according to any one of claims 48 to 79, characterized in that the method further comprises administering TMZ and / or doxorubicin to the subject.

81. A method according to any one of claims 1 to 80, characterized in that the method attenuates tumor growth in the subject.

82. A method according to any one of claims 1 to 81, characterized in that the subject is immunocompetent or immunocompromised.

83. Method according to claim 1, characterized in that i) the tumor-associated macrophage targeting fraction (TAM) is a CD206 targeting fraction; and ii) the active component is coupled to the glucan backbone via a payload ligand, wherein the active component is MMAE and the payload ligand is a Val-Cit ligand.

84. Method according to any one of claims 48 to 50, characterized in that i) the tumor-associated macrophage (TAM) targeting fraction is a CD206 targeting fraction; and ii) the active component is coupled to the glucan backbone via a payload ligand, wherein the active component is MMAE and the payload ligand is a Val-Cit ligand.

85. Method according to claim 1, characterized in that the method comprises administering Compound A to the subject.

86. Method according to any one of claims 48 to 50, characterized in that the method comprises administering Compound A to the subject.

87. Kit, characterized in that it comprises a composition comprising a compound, wherein the compound comprises: i) a tumor-associated macrophage (TAM) targeting fraction; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting fraction to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain fraction and wherein the carbamate group is connected to the backbone monomer and the chain fraction connects the carbamate group and the tumor-associated macrophage targeting fraction; and instructions for administration to a subject for the treatment of a cancer. Petition 870250074096, dated 08 / 21 / 2025, pp. 93 / 108

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